ORCID Profile
0000-0001-6332-4043
Current Organisations
University of Gothenburg
,
University of Western Australia
,
Uppsala University
,
The Harry Perkins Institute of Medical Research
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Publisher: Springer Science and Business Media LLC
Date: 20-04-2020
DOI: 10.1038/S41467-020-15606-0
Abstract: Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has a high mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3 , TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930565.V1
Abstract: b A, /b Kaplan–Meier analysis showing PFS of all patients. b B, /b Kaplan–Meier analysis showing OS of all patients except one. b C, /b Swimmer plot showing time on treatment, time to best response, and duration of response in all patients who received at least one dose of study drug ( i n /i = 29) are shown. b D, /b Kaplan–Meier analysis comparing OS between patients with LDH baseline greater or lower than the upper limit of normal (ULN).
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930547
Abstract: IHC magenta showing low mag of CD20 varied staining of TLS-like (borderline-tertiary lymphoid structures) followed by high magnification images of CD20, CD3, CCL21 within serial sections for Pt 2-027 ( b A /b ), 3-010 ( b B /b ). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . Low and high magnification images of CD20 sup + /sup TLS-like staining for Pt. 2-026 ( b C /b ) and no TLS s le Pt. 4-017 ( b D /b ). Kaplan–Meier analysis showing PFS ( b E /b ) and OS ( b F /b ), respectively iding patient population into two groups based on IHC, no-TLS ( i n /i = 4) and TLS-like ( i n /i = 18). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . b G, /b Heatmap showing top 10% genes with highest log sub /sub fold change, among all positively and negatively significantly regulated genes comparing no-TLS and TLS-like groups using bulk RNA-seq (log sub /sub Reads Per Kilobase per Million mapped reads [RPKM] normalized values). Arrows represent relevant TLS-based gene signatures. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b H, /b In idual box plots showing i CCL19 /i , i CCL21 /i , i CCR7 /i , and i CD79A /i changes in expression between the groups. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745487.V1
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930523.V1
Abstract: Representativeness Table
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930508
Abstract: GSEA
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930517.V1
Abstract: Patient s le information
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745469
Abstract: Representativeness Table
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.ANNONC.2019.11.002
Abstract: The mouse strains usually used to generate patient-derived xenografts (PDXs) are immunocompromised, rendering them unsuitable for immunotherapy studies. Here we assessed the value of immune-PDX mouse models for predicting responses to anti-PD-1 checkpoint inhibitor therapy in patients. Melanoma biopsies contained in a retrospective biobank were transplanted into NOG mice or NOG mice expressing interleukin 2 (hIL2-NOG mice). Tumor growth was monitored, and comparisons were made with clinical data, sequencing data, and current in silico predictive tools. Biopsies grew readily in NOG mice but growth was heterogeneous in hIL2-NOG mice. IL2 appears to activate T-cell immunity in the biopsies to block tumor growth. Biopsy growth in hIL2-NOG mice was negatively associated with survival in patients previously treated with PD-1 checkpoint blockade. In two cases, the prospective clinical decisions of anti-PD-1 therapy or targeted BRAF/MEK inhibitors were supported by the observed responses in mice. Immune-PDX models represent a promising addition to future biomarker discovery studies and for clinical decision making in patients receiving immunotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930559.V1
Abstract: b A, /b Heatmap showing TK1 activity value (DuA) from PEMDAC patient plasma s les, grouped within response groups. Each square is a timepoint for each patient and shows TK1 levels from pretreatment to end of study, until otherwise stated. Total plasma s les analyzed for TK1 = 287. b B, /b Longitudinal TK1 activity for in idual patients, as shown in A. b C /b and b D, /b Kaplan–Meier analysis showing PFS and OS, respectively for pretreatment TK1 values using a threshold of 150 DuA (median TK1 for all s les = 113). Patients with nonavailability of pretreatment s les were excluded from the analysis. b E, /b IHC of TK1 showing nuclear/cytoplasmic magenta staining in patient biopsies 2-027, 3-012, and 3-010. b F, /b Comparison between pretreatment TK1 values for short- and long-term survivors. b G, /b Correlation between pretreatment TK1 (DuA) and circulating tumor DNA (counts/mL) matched patient s les ( i n /i = 21). All statistical tests were unpaired two-tailed i t /i tests, assuming equal variance, with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745460.V1
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745466
Abstract: Baseline characteristics, patient population
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930541
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930544
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745463
Abstract: Patient s le information
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.C.6628509
Abstract: Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for i BAP1 /i tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745472
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930556.V1
Abstract: b A, /b Heatmap of 71 chemokines and cytokines analyzed among all patients and their respective timepoints. Total plasma s les analyzed = 287. Each square represents a timepoint for each patient and shows response group-based levels from pretreatment until end of study, unless otherwise stated. b B, /b Heatmap showing differential pretreatment values between PD and partial responders. Boxed chemokines are significant ( i P /i sub adjusted /sub 0.05) after FDR correction. b C, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups. Only significantly different chemokines from B are included. b D, /b Fold change difference between pretreatment values and week 9 after start of treatment are shown for PD patients. Arrows indicate chemokines that are significant ( i P /i sub adjusted /sub 0.05) after FDR correction between patients that survived longer and those that survived shorter. b E, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups, only significant differences from D are included. Statistical tests in bar charts were unpaired two-tailed i t /i tests (C), assuming unequal variance, or paired i t /i tests (D) with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745478.V1
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745484.V1
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930562.V1
Abstract: b A /b and b B, /b Kaplan–Meier analysis showing PFS and OS of patients with a wildtype i BAP1 /i status and UV-damaged uveal melanoma genome. PFS ( b C /b ) and OS ( b D /b ) analyses comparing patients with GNAQ- or GNA11-mutated uveal melanoma. b E, /b Volcano plot showing differentially expressed genes between short term ( i n /i = 16) and long term (alive patients, i n /i = 4) from bulk RNA-seq. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b F, /b In idual box plots showing relevant gene signatures implicating long-term (alive patients) survival. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: Elsevier BV
Date: 2022
Publisher: Proceedings of the National Academy of Sciences
Date: 16-11-2016
Abstract: Structural changes in chromosomes can alter the expression and function of genes in tumors, an important driving mechanism in some tumors. Whole-genome sequencing makes it possible to detect such events on a genome-wide scale, but comprehensive investigations are still missing. Here, enabled by a massive amount of whole-genome sequencing data generated by The Cancer Genome Atlas consortium, we map somatic structural changes in 600 tumors of erse origins. At a global level, we find that such events often contribute to altered gene expression in human cancer, and also highlight specific events that may have functional roles during tumor development.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2021
DOI: 10.1038/S41467-021-25332-W
Abstract: Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial ( n = 29 NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM. Trial registration ClinicalTrials.gov registration number: NCT02697630 (registered 3 March 2016). EudraCT registration number: 2016–002114-50.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930535
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930520.V1
Abstract: Baseline characteristics, patient population
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930538
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930541.V1
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745463.V1
Abstract: Patient s le information
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745478
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745475
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930532
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745481
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.BIOMATERIALS.2019.119705
Abstract: Tumor cells interact with the microenvironment that specifically supports and promotes tumor development. Key components in the tumor environment have been linked to various aggressive cancer features and can further influence the presence of subpopulations of cancer cells with specific functions, including cancer stem cells and migratory cells. To model and further understand the influence of specific microenvironments we have developed an experimental platform using cell-free patient-derived scaffolds (PDSs) from primary breast cancers infiltrated with standardized breast cancer cell lines. This PDS culture system induced a series of orchestrated changes in differentiation, epithelial-mesenchymal transition, stemness and proliferation of the cancer cell population, where an increased cancer stem cell pool was confirmed using functional assays. Furthermore, global gene expression profiling showed that PDS cultures were similar to xenograft cultures. Mass spectrometry analyses of cell-free PDSs identified subgroups based on their protein composition that were linked to clinical properties, including tumor grade. Finally, we observed that an induction of epithelial-mesenchymal transition-related genes in cancer cells growing on the PDSs were significantly associated with clinical disease recurrences in breast cancer patients. Patient-derived scaffolds thus mimics in vivo-like growth conditions and uncovers unique information about the malignancy-inducing properties of tumor microenvironment.
Publisher: Springer Science and Business Media LLC
Date: 11-10-2019
DOI: 10.1038/S41598-019-51205-W
Abstract: The mut-T homolog-1 (MTH1) inhibitor TH588 has shown promise in preclinical cancer studies but its targeting specificity has been questioned. Alternative mechanisms for the anti-cancer effects of TH588 have been suggested but the question remains unresolved. Here, we performed an unbiased CRISPR screen on human lung cancer cells to identify potential mechanisms behind the cytotoxic effect of TH588. The screen identified pathways and complexes involved in mitotic spindle regulation. Using immunofluorescence and live cell imaging, we showed that TH588 rapidly reduced microtubule plus-end mobility, disrupted mitotic spindles, and prolonged mitosis in a concentration-dependent but MTH1-independent manner. These effects activated a USP28-p53 pathway – the mitotic surveillance pathway – that blocked cell cycle reentry after prolonged mitosis USP28 acted upstream of p53 to arrest TH588-treated cells in the G1-phase of the cell cycle. We conclude that TH588 is a microtubule-modulating agent that activates the mitotic surveillance pathway and thus prevents cancer cells from re-entering the cell cycle.
Publisher: MDPI AG
Date: 20-01-2023
Abstract: Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor s les and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
Publisher: MDPI AG
Date: 26-08-2021
Abstract: Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.C.6628509.V2
Abstract: Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for i BAP1 /i tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.C.6628509.V1
Abstract: Abstract Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the HDAC inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the two-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Results: Durable responses were observed in four patients, with additional eight patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared to those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. /
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930523
Abstract: Representativeness Table
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930544.V1
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: Elsevier BV
Date: 11-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745472.V1
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745466.V1
Abstract: Baseline characteristics, patient population
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930529
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: Frontiers Media SA
Date: 22-05-2019
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930538.V1
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930562
Abstract: b A /b and b B, /b Kaplan–Meier analysis showing PFS and OS of patients with a wildtype i BAP1 /i status and UV-damaged uveal melanoma genome. PFS ( b C /b ) and OS ( b D /b ) analyses comparing patients with GNAQ- or GNA11-mutated uveal melanoma. b E, /b Volcano plot showing differentially expressed genes between short term ( i n /i = 16) and long term (alive patients, i n /i = 4) from bulk RNA-seq. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b F, /b In idual box plots showing relevant gene signatures implicating long-term (alive patients) survival. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745487
Abstract: Figure S1. a) Time To Response (TTR) according to RECIST 1.1. b) Duration of Response (DOR) according to RECIST 1.1. c) Quality of life assessments: Boxplot of EQ-5D VAS evaluation, screening and last known assessment at database lock. d) EQ-5D VAS, change from screening to last known assessment. e) The functional Assessment of Cancer Therapy – General (FACT-G) score sub-scales at screening and at last known assessments
Publisher: American Association for Cancer Research (AACR)
Date: 20-05-2013
DOI: 10.1158/2767-9764.22930520
Abstract: Baseline characteristics, patient population
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.JMB.2017.10.011
Abstract: The highly fine-tuned dynamics of cell cycle gene expression have been intensely studied for several decades. However, some previous observations may be difficult to fully decouple from artifacts induced by traditional cell synchronization procedures. In addition, bulk cell measurements may have disguised intricate details. Here, we address this by sorting and transcriptomic sequencing of single cells progressing through the cell cycle without prior synchronization. Genes and pathways with known cell cycle roles are confirmed, associated regulatory sequence motifs are determined, and we also establish ties between other biological processes and the unsynchronized cell cycle. Importantly, we find the G1 phase to be surprisingly heterogeneous, with transcriptionally distinct early and late time points. We additionally note that mRNAs accumulate to reach maximum total levels at mitosis and find that stable transcripts show reduced cell-to-cell variability, consistent with the transcriptional burst model of gene expression. Our study provides the first detailed transcriptional profiling of an unsynchronized human cell cycle.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745484
Abstract: Figure S2. a) Gene signatures implicating short term survival. Statistical tests were carried out using DESeq2 and FDR-adjusted P-values were denoted with *, P 0.05 **, P 0.01 ***, P 0.001. b) Average of TK1 values assessed for all timepoints by the number of timepoints ided among response groups, PD, SD, PR. c) TK1 values in different response groups
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930565
Abstract: b A, /b Kaplan–Meier analysis showing PFS of all patients. b B, /b Kaplan–Meier analysis showing OS of all patients except one. b C, /b Swimmer plot showing time on treatment, time to best response, and duration of response in all patients who received at least one dose of study drug ( i n /i = 29) are shown. b D, /b Kaplan–Meier analysis comparing OS between patients with LDH baseline greater or lower than the upper limit of normal (ULN).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-11-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745457.V1
Abstract: Complete differential expression results
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930535.V1
Abstract: Figure S4. Kaplan–Meier analysis showing PFS of a) CCL13 and b) IL-21. c) Flow cytometry plots showing CCR7 and CD45RA gating among CD3 positive cells in blood s les d) Flow cytometry based comparison between short (n=18) and long (n=6) term survivors with CD3+CCR7+ % (T naive, T stem cell memory and T central memory) analysis using pretreatment blood s les and e) Kaplan–Meier analysis showing Overall survival with median CD3+CCR7+ % (n=24).
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930547.V1
Abstract: IHC magenta showing low mag of CD20 varied staining of TLS-like (borderline-tertiary lymphoid structures) followed by high magnification images of CD20, CD3, CCL21 within serial sections for Pt 2-027 ( b A /b ), 3-010 ( b B /b ). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . Low and high magnification images of CD20 sup + /sup TLS-like staining for Pt. 2-026 ( b C /b ) and no TLS s le Pt. 4-017 ( b D /b ). Kaplan–Meier analysis showing PFS ( b E /b ) and OS ( b F /b ), respectively iding patient population into two groups based on IHC, no-TLS ( i n /i = 4) and TLS-like ( i n /i = 18). Also see a href="#SMF5" target="_blank" Supplementary Fig. S5 /a . b G, /b Heatmap showing top 10% genes with highest log sub /sub fold change, among all positively and negatively significantly regulated genes comparing no-TLS and TLS-like groups using bulk RNA-seq (log sub /sub Reads Per Kilobase per Million mapped reads [RPKM] normalized values). Arrows represent relevant TLS-based gene signatures. Genes with FDR-adjusted i P /i values .05 were considered statistically significant. b H, /b In idual box plots showing i CCL19 /i , i CCL21 /i , i CCR7 /i , and i CD79A /i changes in expression between the groups. Statistical tests were carried out using DESeq2 and FDR-adjusted i P /i values were denoted with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2018
DOI: 10.1200/PO.18.00002
Abstract: Cancer of unknown primary is a group of metastatic tumors in which the standard diagnostic workup fails to identify the site of origin of the tumor. The potential impact of precision oncology on this group of patients is large, because actionable driver mutations and a correct diagnosis could provide treatment options otherwise not available for patients with these fatal cancers. This study investigated if comprehensive genomic analyses could provide information on the origin of the tumor. Here we describe a patient whose tumor was misdiagnosed at least three times. Next-generation sequencing, a patient-derived xenograft mouse model, and bioinformatics were used to identify an actionable mutation, predict resistance development to the targeted therapy, and correctly diagnose the origin of the tumor. Transcriptomic classification was benchmarked using The Cancer Genome Atlas (TCGA). Despite the lack of a known primary tumor site and the absence of diagnostic immunohistochemical markers, the origin of the patient’s tumor was established using the novel bioinformatic workflow. This included a mutational signature analysis of the sequenced metastases and comparison of their transcriptomic profiles to a pan-cancer panel of tumors from TCGA. We further discuss the strengths and limitations of the latter approaches in the context of three potentially incorrectly diagnosed TCGA lung tumors. Comprehensive genomic analyses can provide information on the origin of tumors in patients with cancer of unknown primary.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-10-2018
DOI: 10.1161/CIRCULATIONAHA.117.032184
Abstract: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E–deficient ( ApoE −/− ) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription–polymerase chain reaction and in situ hybridization. Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue s les, and in a novel preclinical LDLR −/− (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1α as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1α and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1α via recruiting the transcription factor specificity protein 1 to the promoter region. The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2018
DOI: 10.1038/S41419-018-0865-6
Abstract: Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could ide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1 , which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not h er T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930556
Abstract: b A, /b Heatmap of 71 chemokines and cytokines analyzed among all patients and their respective timepoints. Total plasma s les analyzed = 287. Each square represents a timepoint for each patient and shows response group-based levels from pretreatment until end of study, unless otherwise stated. b B, /b Heatmap showing differential pretreatment values between PD and partial responders. Boxed chemokines are significant ( i P /i sub adjusted /sub 0.05) after FDR correction. b C, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups. Only significantly different chemokines from B are included. b D, /b Fold change difference between pretreatment values and week 9 after start of treatment are shown for PD patients. Arrows indicate chemokines that are significant ( i P /i sub adjusted /sub 0.05) after FDR correction between patients that survived longer and those that survived shorter. b E, /b In idual chemokine or cytokine values (pg/mL) compared among different response groups, only significant differences from D are included. Statistical tests in bar charts were unpaired two-tailed i t /i tests (C), assuming unequal variance, or paired i t /i tests (D) with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: Cold Spring Harbor Laboratory
Date: 18-05-2023
DOI: 10.1101/2023.05.16.540908
Abstract: Uveal melanoma (UM) is a rare melanoma originating in the eye’s uvea, with 50% of patients experiencing metastasis predominantly in the liver. In contrast to cutaneous melanoma, there is only a limited effectiveness of combined immune checkpoint therapies, and half of patients succumb to recurrent disease after two years. This study aimed to provide a path towards enhancing immunotherapy efficacy by identifying and functionally validating tumor-reactive T cells in liver metastases of patients with UM. We employed single-cell RNA sequencing of biopsies and tumor-infiltrating lymphocytes (TILs) to identify potential tumor-reactive T cells. Patient-derived xenograft (PDX) models of UM metastases were created from patients, and tumor sphere cultures were generated from these models for co-culture with autologous or MART1-specific HLA-matched allogenic TILs. Activated T cells were subjected to TCR sequencing, and the TCRs were matched to those found in single-cell sequencing data from biopsies and expanded TILs. Our findings revealed that tumor-reactive T cells resided not only among activated and exhausted subsets of T cells, but also in a subset of cytotoxic effector cells. In conclusion, combining single-cell sequencing and functional analysis provides valuable insights into which T cells in UM may be useful for cell therapy lification and marker selection.
Publisher: Oxford University Press (OUP)
Date: 29-07-2016
DOI: 10.1093/NAR/GKW674
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930559
Abstract: b A, /b Heatmap showing TK1 activity value (DuA) from PEMDAC patient plasma s les, grouped within response groups. Each square is a timepoint for each patient and shows TK1 levels from pretreatment to end of study, until otherwise stated. Total plasma s les analyzed for TK1 = 287. b B, /b Longitudinal TK1 activity for in idual patients, as shown in A. b C /b and b D, /b Kaplan–Meier analysis showing PFS and OS, respectively for pretreatment TK1 values using a threshold of 150 DuA (median TK1 for all s les = 113). Patients with nonavailability of pretreatment s les were excluded from the analysis. b E, /b IHC of TK1 showing nuclear/cytoplasmic magenta staining in patient biopsies 2-027, 3-012, and 3-010. b F, /b Comparison between pretreatment TK1 values for short- and long-term survivors. b G, /b Correlation between pretreatment TK1 (DuA) and circulating tumor DNA (counts/mL) matched patient s les ( i n /i = 21). All statistical tests were unpaired two-tailed i t /i tests, assuming equal variance, with *, i P /i 0.05 **, i P /i 0.01 ***, i P /i 0.001.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930514
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930517
Abstract: Patient s le information
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745469.V1
Abstract: Representativeness Table
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930514.V1
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: Elsevier BV
Date: 10-2022
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745457
Abstract: Complete differential expression results
Publisher: Frontiers Media SA
Date: 09-03-2022
DOI: 10.3389/FIMMU.2022.813203
Abstract: B cells interact with T follicular helper (Tfh) cells in germinal centers (GCs) to generate high-affinity antibodies. Much less is known about how cognate T–B-cell interactions influence Th cells that enter circulation and peripheral tissues. Therefore, we generated mice lacking MHC-II expressing B cells and, by thoracic duct cannulation, analyzed Th cells in the efferent lymph at defined intervals post-immunization. Focusing on gut-draining mesenteric lymph nodes (MLNs), we show that antigen-specific α 4 β 7 + gut-homing effector Th cells enter the circulation prior to CXCR5 + PD-1 + Tfh-like cells. B cells appear to have no or limited impact on the early generation and egress of gut-homing Th cells but are critical for the subsequent appearance of Tfh-like cells that peak in the lymph before GCs have developed. At this stage, antigen-presenting B cells also reduce the proportion of α 4 β 7 + Th cells in the MLN and efferent lymph. Furthermore, cognate B-cell interaction drives a broad transcriptional program in Th cells, including IL-4 that is confined to the Tfh cell lineage. The IL-4-producing Tfh-like cells originate from Bcl6 + precursors in the LNs and have gut-homing capacity. Hence, B cells program the efferent lymph Th cell response within a limited window of time after antigenic challenge.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745454
Abstract: GSEA
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930553
Abstract: Kaplan–Meier analysis showing. PFS ( b A /b ) and OS ( b B /b ), respectively using pretreatment plasma CCL21 (pg/mL) measurements based on their median values. b C, /b Correlation between CCL21 (pg/mL) and CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup (% counts) matched patient s les ( i n /i = 23). b D, /b Flow cytometry–based comparison between short- and long-term survivors for CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % (T naïve and T stem cell memory) analysis using pretreatment blood s les ( i n /i = 24). Statistical test was unpaired two-tailed i t /i tests, assuming equal variance. b E, /b Kaplan–Meier analysis showing OS using median CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % values.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930511
Abstract: Complete differential expression results
Publisher: Public Library of Science (PLoS)
Date: 03-01-2023
DOI: 10.1371/JOURNAL.PONE.0279578
Abstract: The SARS-CoV-2 virus is currently causing a global pandemic. Infection may result in a systemic disease called COVID-19, affecting primarily the respiratory tract. Often the gastrointestinal tract and kidneys also become involved. Angiotensin converting enzyme 2 (ACE2) serves as the receptor for SARS-CoV-2. The membrane proteins, Transmembrane serine protease 2 (TMPRSS2) and Neuropilin 1 (NRP1) are accessory proteins facilitating the virus entry. In this study we show that the human proximal kidney tubules, express these factors. We hypothesized that cancers derived from proximal tubules as clear cell (CCRCC) and papillary renal cell carcinoma (PRCC), retain the expression of the SARS-CoV-2 entry factors making these cancers susceptible to SARS-CoV-2 infection. We used bioinformatics, western blotting, and assessment of tissue micro arrays (TMA) including 263 cases of CCRCC, 139 cases of PRCC and 18 cases of chromophobe RCC to demonstrate that the majority of CCRCC and PRCC cases retained the RNA and protein expression of the entry factors for SARS-CoV-2. We furthermore show that SARS-CoV-2 virus propagated robustly in primary cultures of CCRCC and PRCC cells with a visible virus cytopathogenic effect correlating with viral RNA expression levels. We also noted that the delta-variant of SARS-CoV-2 causes cancer cells to form syncytia in-vitro . This phenomenon was also identified histologically in CCRCC tissue from a patient that had been hospitalized for COVID-19, twelve months prior to nephrectomy. Our data provide insights into SARS-CoV-2 infectivity in renal cell carcinoma and that the virus causes a distinct cytopathogenic effect.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930529.V1
Abstract: Figure S6. Analysis of clinical parameters gender (a), tumor BAP1 status (b) and LDH levels (c-d) compared to serum levels of CCL21 (a-c) or presence of TLS-like regions in tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745481.V1
Abstract: Figure S3. a) Heat map showing plasma chemokine and cytokine levels pre-treatment to end of study (EOS) in patients with progressive disease (PD) b) Heat map of plasma chemokine levels pre-treatment to EOS in stable disease (SD) patients. c) Heat map of plasma chemokine levels pre-treatment to EOS in partial response (PR) patients d) Levels of CXCL9 in different response groups pretreatment and EOS. e) Levels of CXCL9 pretreatment and EOS in patients surviving longer or shorter in the PEMDAC trail.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745460
Abstract: Follow up adverse events (AE) of grade ≥3 (n = 29 patients)
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745454.V1
Abstract: GSEA
Publisher: Springer Science and Business Media LLC
Date: 06-02-2020
DOI: 10.1038/S41419-020-2301-Y
Abstract: On Pubmed, the name of co-author Roger Olofsson Bagge appeared incorrectly as “Bagge RO” instead of “Olofsson Bagge, Roger”. This has been corrected in the PDF and HTML versions.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930553.V1
Abstract: Kaplan–Meier analysis showing. PFS ( b A /b ) and OS ( b B /b ), respectively using pretreatment plasma CCL21 (pg/mL) measurements based on their median values. b C, /b Correlation between CCL21 (pg/mL) and CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup (% counts) matched patient s les ( i n /i = 23). b D, /b Flow cytometry–based comparison between short- and long-term survivors for CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % (T naïve and T stem cell memory) analysis using pretreatment blood s les ( i n /i = 24). Statistical test was unpaired two-tailed i t /i tests, assuming equal variance. b E, /b Kaplan–Meier analysis showing OS using median CD3 sup + /sup CCR7 sup + /sup CD45RA sup + /sup % values.
Publisher: American Association for Cancer Research (AACR)
Date: 03-05-2023
DOI: 10.1158/2767-9764.22745475.V1
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.CRC-22-0490
Abstract: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930532.V1
Abstract: Figure S5. Immunohistochemistry magenta of a) Immunohistochemistry magenta showing CCL21 and corresponding CCR7 expression within tumor biopsies for patient 1-013 and 3-009. b) Patient 1-013, a lymph node biopsy showing CD20, CD3 and CCL21 staining with serial sections. c) Patient 2-027, a liver met biopsy showing SOX10, CCR7, TK1 and PDL1 (DAB) within the same areas as shown in Fig 6.
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930508.V1
Abstract: GSEA
Publisher: American Association for Cancer Research (AACR)
Date: 18-05-2023
DOI: 10.1158/2767-9764.22930511.V1
Abstract: Complete differential expression results
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2019
DOI: 10.1101/742023
Abstract: Uveal melanoma (UM) is a rare form of melanoma with a genetics and immunology that is different from skin melanoma. Previous studies have identified genetic driver events of early stage disease when the tumor is confined to the eye. However due to lack of a clinical rationale to biopsy metastatic disease, access to tumor material to perform molecular profiling of metastases has been limited. In this study, we have characterized genomic events in UM metastases using whole-genome sequencing of fresh frozen biopsies from thirty-two patients and profiled the transcriptomes of in idual tumor infiltrating lymphocytes in eight patients by single-cell sequencing. We find that 91% of the patients have metastases carrying inactivating events in the tumor suppressor BAP1 and this coincided with somatic alterations in GNAQ , GNA11 , CYSLTR2 , PLCB4 , SF3B1 and/or CDKN2A . Mutational signature analysis revealed a rare subset of tumors with prominent signs of UV damage, associated with outlier mutational burden. We study copy number variations (CNV) and find overrepresented events, some of which were not altered in matched primary eye tumors. A focused siRNA screen identified functionally significant genes of some of the segments recurrently gained. We reintroduced a functional copy of BAP1 into a patient-derived BAP1 deficient tumor cell line and found broad transcriptomic changes of genes associated with subtype distinction and prognosis in primary UM. Lastly, our analysis of the immune microenvironments of metastases revealed a presence of tumor-reactive T cells. However, a majority expressed the immune checkpoint receptors TIM-3, LAG3 and TIGIT, and to a lesser extent PD-1. These results provide an updated view of genomic events represented in metastatic UM and immune interactions in advanced lesions.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2019
No related grants have been discovered for Joakim Karlsson.