ORCID Profile
0000-0003-2473-5565
Current Organisations
University of Essen
,
Herzzentrum Essen-Huttrop
,
Melanoma Institute Australia
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627309.V1
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490746.V1
Abstract: Clinical and mIHC data generated within the study.
Publisher: Oxford University Press (OUP)
Date: 02-2021
DOI: 10.1093/CVR/CVAB024
Abstract: Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the ‘NACHT, LRR, and PYD Domains-containing Protein 3’ (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF. Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3−/−) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3−/− mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3−/−) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice. These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488771
Abstract: Integrated gene set enrichment analysis by body mass index (BMI) with correction for S phase. This figure presents a dotplot of genes differentially up- or downregulated in OW/OB patients versus NL BMI patients. Red indicates upregulation in OW/OB verse NL. The far left column is all patients, and then, an analysis controlling for sex, cohort, and tissue site is shown in the 3 columns to the right.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490752.V1
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627315.V1
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488735.V1
Abstract: Body mass index values by patient ID for all RNASeq cohorts.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488732
Abstract: RNASeq data for the MDA cohort (n=61) with associated clinical info.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488768
Abstract: Reverse phase protein array of the PI3K pathway expression by BMI. Box plot represents the median bar with the box bounding IQR and whiskers the minimum and maximum values.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1038/MODPATHOL.2017.89
Abstract: Understanding the mechanisms of acquired resistance to anti-PD-1 will allow development of better treatment strategies for cancer patients. This study evaluated potential mechanisms of acquired resistance to anti-PD-1 in longitudinally collected metastatic melanoma patient biopsies. Thirty-four metastatic melanoma biopsies were collected from 16 patients who had initially responded to either anti-PD-1 (n=13) alone or combination of anti-PD-1 and ipilimumab (n=3) and then progressed. Biopsies were taken prior to treatment (PRE, n=12) and following progression of disease (PROG, n=22). Immunohistochemistry was performed on all biopsies to detect CD8, FOXP3, PD-1 and VISTA expression on T-cells and PTEN, β-catenin, PD-L1, HLA-A, and HLA-DPB1 expression in the tumor. The majority of patients showed significantly increased density of VISTA+ lymphocytes from PRE to PROG (12/18) (P=0.009) and increased expression of tumor PD-L1 from PRE to PROG (11/18). Intratumoral expression of FOXP3+ lymphocytes significantly increased (P=0.018) from PRE to PROG (10/18). Loss of tumor PTEN and downregulation of tumor HLA-A from PRE to PROG were each identified in 5/18 and 4/18 PROG biopsies, respectively. Downregulation of HLA-DPB1 from PRE to PROG was present in 3/18 PROG biopsies, whereas nuclear β-catenin activation was only identified in 2/18 PROG biopsies. Negative immune checkpoint regulation by VISTA represents an important potential mechanism of acquired resistance in melanoma patients treated with anti-PD-1. Downregulation of HLA-associated antigen presentation also occurs with acquired resistance. Augmentation of the VISTA immune checkpoint pathway may hold promise as a therapeutic strategy in metastatic melanoma patients, particularly those failing anti-PD-1 therapy, and warrants assessment in clinical trials.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488729
Abstract: Supplementary Table 1: Baseline characteristics for patients included in the integrated gene set enrichment analysis (Figure 2-3) by cohort Supplementary Table 6: The most frequent somatic alterations (alts) in patients with regionally metastatic melanoma by body mass index from The Cancer Genome Atlas cohort Supplemental Table 7: Integrated gene set enrichment analysis for pathways associated with fatty acid metabolism by body mass index Supplemental Table 8: Gene expression of selected genes of interest involved in fatty acid metabolism.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2023
DOI: 10.1158/1078-0432.CCR-22-2657
Abstract: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival. Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes. Patients who responded to combination immune checkpoint inhibitor contained higher CD16+ macrophage densities than those who did not respond (196 vs. 7 cells/mm2 P = 0.0041). There was no diffidence in CD16+ macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm2 P = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16+ macrophages compared with those with low densities (87% vs. 42%, P = 0.0056, n = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, P = 0.4636, n = 50). Melanoma biopsies with high densities of CD16+ macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10, and CXCL11). Our data demonstrate that tumor microenvironments enriched with CD16+ macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. See related commentary by Smithy and Luke, p. 2345
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488768.V1
Abstract: Reverse phase protein array of the PI3K pathway expression by BMI. Box plot represents the median bar with the box bounding IQR and whiskers the minimum and maximum values.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490761
Abstract: Cohort and dataset overview
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490749.V1
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: MDPI AG
Date: 25-06-2021
Abstract: While immune checkpoint inhibitors targeting the CTLA-4 and PD-1 receptors have significantly improved outcomes of many patients with metastatic melanoma, there remains a group of patients who demonstrate no benefit. In this study, we sought to characterise patients who do not respond to anti-PD-1-based therapies based on their clinical, genetic and immune profiles. Forty patients with metastatic melanoma who did not respond to anti-PD-1 +/− anti-CTLA-4 treatment were identified. Targeted RNA sequencing (n = 37) was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Patients clustered into two groups based on the expression profiles of 26 differentially expressed genes: an immune gene rich group (n = 17) expressing genes associated with immune and T cell signalling, and a second group (n = 20) expressing genes associated with metabolism, signal transduction and neuronal signalling. Multiplex immunohistochemistry validated significantly higher densities of tumour-infiltrating lymphocytes (TILs) and macrophages in the immune gene-rich group. This TIL-high subset of patients also demonstrated higher expression of alternative immune-regulatory drug targets compared to the TIL-low group. Patients were also sub ided into rapid progressors and other progressors (cut-off 2 mo progression-free survival), with significantly lower TILs (p = 0.04) and CD68+ macrophages (p = 0.0091) in the rapid progressors. Furthermore, a trend towards a higher tumour burden was observed in rapid progressors (p = 0.06). These data highlight the need for a personalised and multilayer (clinical and molecular) approach for identifying the most appropriate treatments for anti-PD-1 resistant patients and provides insight into how in idual treatment strategies can be achieved.
Publisher: Informa UK Limited
Date: 04-10-2023
Publisher: Springer Science and Business Media LLC
Date: 13-04-2023
DOI: 10.1186/S12967-023-04092-9
Abstract: Gene expression profiling is increasingly being utilised as a diagnostic, prognostic and predictive tool for managing cancer patients. Single-s le scoring approach has been developed to alleviate instability of signature scores due to variations from s le composition. However, it is a challenge to achieve comparable signature scores across different expressional platforms. The pre-treatment biopsies from a total of 158 patients, who have received single-agent anti-PD-1 (n = 84) or anti-PD-1 + anti-CTLA-4 therapy (n = 74), were performed using NanoString PanCancer IO360 Panel. Multiple immune-related signature scores were measured from a single-s le rank-based scoring approach, singscore . We assessed the reproducibility and the performance in reporting immune profile of singscore based on NanoString assay in advance melanoma. To conduct cross-platform analyses, singscores between the immune profiles of NanoString assay and the previous orthogonal whole transcriptome sequencing (WTS) data were compared through linear regression and cross-platform prediction. singscore -derived signature scores reported significantly high scores in responders in multiple PD-1, MHC-1-, CD8 T-cell-, antigen presentation-, cytokine- and chemokine-related signatures. We found that singscore provided stable and reproducible signature scores among the repeats in different batches and cross-s le normalisations. The cross-platform comparisons confirmed that singscores derived via NanoString and WTS were comparable. When singscore of WTS generated by the overlapping genes to the NanoString gene set, the signatures generated highly correlated cross-platform scores (Spearman correlation interquartile range (IQR) [0.88, 0.92] and r 2 IQR [0.77, 0.81]) and better prediction on cross-platform response (AUC = 86.3%). The model suggested that Tumour Inflammation Signature (TIS) and Personalised Immunotherapy Platform (PIP) PD-1 are informative signatures for predicting immunotherapy-response outcomes in advanced melanoma patients treated with anti-PD-1-based therapies. Overall, the outcome of this study confirms that singscore based on NanoString data is a feasible approach to produce reliable signature scores for determining patients’ immune profiles and the potential clinical utility in biomarker implementation, as well as to conduct cross-platform comparisons, such as WTS.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488738.V1
Abstract: Differential gene expression analysis for each subgroup.
Publisher: Informa UK Limited
Date: 31-10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627306.V1
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488765.V1
Abstract: Integrated gene set enrichment analysis of subgroups by body mass index BMI. This figure compares gene expression between overweight/obese (OW/OB) and normal (NL) BMI patients with metastatic melanoma across subgroups by sex, cohort, and tissue site. Supplementary Figure 2 presents a dotplot of genes differentially up- or downregulated in OW/OB patients versus NL BMI patients by subgroups. Red indicates upregulation in OW/OB verse NL.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2202
DOI: 10.1158/1078-0432.22488759.V1
Abstract: Immune cell analysis by BMI and sex. A. Immunohistochemistry (IHC) analysis of the MDA cohort stratified by BMI and sex. Line represents median +/- interquartile range each dot represents a single tumor. B. IHC analysis of the Gide cohort stratified by BMI and sex. Line represents median +/- interquartile range each dot represents a single tumor.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6533212.V1
Abstract: AbstractPurpose: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival. Experimental Design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes. Results: Patients who responded to combination immune checkpoint inhibitor contained higher CD16 sup + /sup macrophage densities than those who did not respond (196 vs. 7 cells/mm sup /sup i P = /i 0.0041). There was no diffidence in CD16 sup + /sup macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm sup /sup i P /i = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16 sup + /sup macrophages compared with those with low densities (87% vs. 42%, i P /i = 0.0056, i n /i = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, i P /i = 0.4636, i n /i = 50). Melanoma biopsies with high densities of CD16 sup + /sup macrophages contained upregulated gene expression of critical T-cell recruiting chemokines ( i CXCL9 /i , i CXCL10 /i , and i CXCL11 /i ). Conclusions: Our data demonstrate that tumor microenvironments enriched with CD16 sup + /sup macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488762
Abstract: Immune cell analysis by BMI. A. Immunohistochemistry (IHC) analysis for CD8-, CD45RO-, FOXP3-, CD68-, GZMB-, PD-1-, LAG-3-, and CD3-positive cells in overweight/obese (OW/OB) verse normal (NL) tumors as defined by body mass index from the MD Anderson Cancer Center (MDA) cohort. Line represents median +/- interquartile range each dot represents a single tumor. B. IHC analysis for PD-L1-, CD45RO-, FOXP3-, EOMES-, GZMB-, PD-1-, TBET-, and TBET:FOXP3-positive cells in OW/OB verse NL tumors as defined by body mass index from the Gide cohort. Line represents median +/- interquartile range each dot represents a single tumor.
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2020
DOI: 10.1158/1078-0432.CCR-19-1868
Abstract: Response rates to immune checkpoint blockade (ICB anti-PD-1/anti-CTLA-4) correlate with the extent of tumor immune infiltrate, but the mechanisms underlying the recruitment of T cells following therapy are poorly characterized. A greater understanding of these processes may see the development of therapeutic interventions that enhance T-cell recruitment and, consequently, improved patient outcomes. We therefore investigated the chemokines essential for immune cell recruitment and subsequent therapeutic efficacy of these immunotherapies. The chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using NanoString-based analysis with results confirmed at the protein level by flow cytometry and cytometric bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using single-cell RNA-sequencing (RNA-seq) and paired survival analyses. The CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD-1/CTLA-4 blockade and both CD8+ T-cell infiltration and therapeutic efficacy were CXCR3 dependent. In both murine models and patients undergoing immunotherapy, macrophages were the predominant source of CXCL9 and their depletion abrogated CD8+ T-cell infiltration and the therapeutic efficacy of dual ICB. Single-cell RNA-seq analysis of patient tumor-infiltrating lymphocytes (TIL) revealed that CXCL9/10/11 was predominantly expressed by macrophages following ICB and we identified a distinct macrophage signature that was associated with positive responses to ICB. These data underline the fundamental importance of macrophage-derived CXCR3 ligands for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient responses.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.C.6533212
Abstract: AbstractPurpose: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival. Experimental Design: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes. Results: Patients who responded to combination immune checkpoint inhibitor contained higher CD16 sup + /sup macrophage densities than those who did not respond (196 vs. 7 cells/mm sup /sup i P = /i 0.0041). There was no diffidence in CD16 sup + /sup macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm sup /sup i P /i = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16 sup + /sup macrophages compared with those with low densities (87% vs. 42%, i P /i = 0.0056, i n /i = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, i P /i = 0.4636, i n /i = 50). Melanoma biopsies with high densities of CD16 sup + /sup macrophages contained upregulated gene expression of critical T-cell recruiting chemokines ( i CXCL9 /i , i CXCL10 /i , and i CXCL11 /i ). Conclusions: Our data demonstrate that tumor microenvironments enriched with CD16 sup + /sup macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-23-0490" target="_blank" See related commentary by Smithy and Luke, p. 2345 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488765
Abstract: Integrated gene set enrichment analysis of subgroups by body mass index BMI. This figure compares gene expression between overweight/obese (OW/OB) and normal (NL) BMI patients with metastatic melanoma across subgroups by sex, cohort, and tissue site. Supplementary Figure 2 presents a dotplot of genes differentially up- or downregulated in OW/OB patients versus NL BMI patients by subgroups. Red indicates upregulation in OW/OB verse NL.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490758.V1
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488771.V1
Abstract: Integrated gene set enrichment analysis by body mass index (BMI) with correction for S phase. This figure presents a dotplot of genes differentially up- or downregulated in OW/OB patients versus NL BMI patients. Red indicates upregulation in OW/OB verse NL. The far left column is all patients, and then, an analysis controlling for sex, cohort, and tissue site is shown in the 3 columns to the right.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627312.V1
Abstract: Representativeness of study participants
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488750.V1
Abstract: Beta- ersity analysis stratified by sex based on Bray-Curtis dissimilarity represents microbiome s les with metastatic melanoma in terms of the two top principal components (explaining around 17% of variance) obtained from the principal coordinate analysis. Red dots are from overweight/obese (OW/OB) BMI patients, and blue dots are from normal (NL) BMI patients. Shading inside the dots indicates the female gender. This is a subgroup analysis of Figure 5B.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490758
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627318
Abstract: Cohort and dataset overview
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488759
Abstract: Immune cell analysis by BMI and sex. A. Immunohistochemistry (IHC) analysis of the MDA cohort stratified by BMI and sex. Line represents median +/- interquartile range each dot represents a single tumor. B. IHC analysis of the Gide cohort stratified by BMI and sex. Line represents median +/- interquartile range each dot represents a single tumor.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490755.V1
Abstract: Representativeness of study participants
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627315
Abstract: C1Q and PD-1 expression on CD16+ macrophages in on treatment biopsies of melanoma patients treated with PD-1 or PD-1+CTLA-4 ICB. Dynamics between pretreatment and early-during treatment biopsies on (a) CD16+ macrophages as a proportion of all macrophages (b) CD16+ C1q+ macrophages as a proportion of all C1q+ macrophages (c) PD-1+ CD16+ macrophages as a proportion of PD-1+ macrophages (d) PD-1+ CD16+ C1q+ macrophages as a proportion of all macrophages (e) C1q+ CD16+ macrophages as a proportion of CD16+ macrophages (f) PD-1+ CD16+ macrophages as a proportion of CD16+ macrophages. (g) Log2 RNA expression of C1qa-c in pretreatment (PRE) and early during treatment (EDT) biopsies of responding and non-responding patients treated with PD-1 or PD-1+CTLA-4 ICB. (h) Flow cytometry analysis of ipilimumab (IgG1) and/or secondary anti-IgG1 binding to CD16+ and CD16- macrophages in a melanoma patient's tumor dissociate. FMO, a no-secondary control.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532803
Abstract: AbstractPurpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts ( i n /i = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients ( i x /i = 36) by LC/MS, and in flow-sorted melanoma tumor cells ( i x /i = 37) and patient-derived melanoma cell lines ( i x /i = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort ( i n /i = 371). Results: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, ersity, and taxonomy of the fecal microbiome did not differ by BMI. Conclusions: These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-3028" target="_blank" See related commentary by Smalley, p. 5 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 12-03-2120
DOI: 10.1158/1078-0432.22488744.V1
Abstract: Differential gene expression analysis for covariates controlled.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490761.V1
Abstract: Cohort and dataset overview
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490755
Abstract: Representativeness of study participants
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490752
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 05-05-2027
DOI: 10.1158/1078-0432.23627312
Abstract: Representativeness of study participants
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488762.V1
Abstract: Immune cell analysis by BMI. A. Immunohistochemistry (IHC) analysis for CD8-, CD45RO-, FOXP3-, CD68-, GZMB-, PD-1-, LAG-3-, and CD3-positive cells in overweight/obese (OW/OB) verse normal (NL) tumors as defined by body mass index from the MD Anderson Cancer Center (MDA) cohort. Line represents median +/- interquartile range each dot represents a single tumor. B. IHC analysis for PD-L1-, CD45RO-, FOXP3-, EOMES-, GZMB-, PD-1-, TBET-, and TBET:FOXP3-positive cells in OW/OB verse NL tumors as defined by body mass index from the Gide cohort. Line represents median +/- interquartile range each dot represents a single tumor.
Publisher: American Society for Clinical Investigation
Date: 08-11-2022
Publisher: Frontiers Media SA
Date: 19-05-2022
DOI: 10.3389/FMOLB.2022.810858
Abstract: Multiplex immunofluorescence staining enables the simultaneous detection of multiple immune markers in a single tissue section, and is a useful tool for the identification of specific cell populations within the tumour microenvironment. However, this technology has rarely been validated against standard clinical immunohistology, which is a barrier for its integration into clinical practice. This study sought to validate and investigate the accuracy, precision and reproducibility of a multiplex immunofluorescence compared with immunohistochemistry (IHC), including tissue staining, imaging and analysis, in characterising the expression of immune and melanoma markers in both the tumour and its microenvironment. Traditional chromogenic IHC, single-plex immunofluorescence and multiplex immunofluorescence were each performed on serial tissue sections of a formalin-fixed paraffin-embedded (FFPE) tissue microarray containing metastatic melanoma specimens from 67 patients. The panel included the immune cell markers CD8, CD68, CD16, the immune checkpoint PD-L1, and melanoma tumour marker SOX10. Slides were stained with the Opal ™ 7 colour Kit (Akoya Biosciences) on the intelliPATH autostainer (Biocare Medical) and imaged using the Vectra 3.0.5 microscope. Marker expression was quantified using Halo v.3.2.181 (Indica Labs). Comparison of the IHC and single-plex immunofluorescence revealed highly significant positive correlations between the cell densities of CD8, CD68, CD16, PD-L1 and SOX10 marker positive cells (Spearman’s rho = 0.927 to 0.750, p & 0.0001). Highly significant correlations were also observed for all markers between single-plex immunofluorescence and multiplex immunofluorescence staining (Spearman’s rho & .9, p & 0.0001). Finally, correlation analysis of the three multiplex replicates revealed a high degree of reproducibility between slides (Spearman’s rho & .940, p & 0.0001). Together, these data highlight the reliability and validity of multiplex immunofluorescence in accurately profiling the tumour and its associated microenvironment using FFPE metastatic melanoma specimens. This validated multiplex panel can be utilised for research evaluating melanoma and its microenvironment, such as studies performed to predict patient response or resistance to immunotherapies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488756.V1
Abstract: Direct metabolite measurements from a subset of The Cancer Genome Atlas (TCGA) cohort. Comparison of additional tricarboxylic acid cycle metabolites measured by liquid chromatography/mass spectrometry between metastatic melanoma tumors from overweight/obese (OW/OB) patients by body mass index (BMI) verse normal (NL) BMI from The Cancer Genome Atlas (TCGA). Lines represent mean +/- SEM each dot represents a single tumor.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488750
Abstract: Beta- ersity analysis stratified by sex based on Bray-Curtis dissimilarity represents microbiome s les with metastatic melanoma in terms of the two top principal components (explaining around 17% of variance) obtained from the principal coordinate analysis. Red dots are from overweight/obese (OW/OB) BMI patients, and blue dots are from normal (NL) BMI patients. Shading inside the dots indicates the female gender. This is a subgroup analysis of Figure 5B.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488756
Abstract: Direct metabolite measurements from a subset of The Cancer Genome Atlas (TCGA) cohort. Comparison of additional tricarboxylic acid cycle metabolites measured by liquid chromatography/mass spectrometry between metastatic melanoma tumors from overweight/obese (OW/OB) patients by body mass index (BMI) verse normal (NL) BMI from The Cancer Genome Atlas (TCGA). Lines represent mean +/- SEM each dot represents a single tumor.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488747
Abstract: Inverse Simpson alpha ersity scores of the fecal microbiome by BMI in patients with metastatic melanoma stratified by sex. Box plot represents the median bar with the box bounding the IQR and whiskers the most extreme points within 1.5 x IQR. The red dots represent OW/OB patients and the blue dots represent NL patients by BMI. This is a subgroup analysis of Figure 5C.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627306
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490746
Abstract: Clinical and mIHC data generated within the study.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22490749
Abstract: Differential expression analysis gene list of FACS sorted CD16+ compared to CD16- macrophages from human melanoma dissociates.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627309
Abstract: Multiplex immunohistochemical staining protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627303.V1
Abstract: Clinical and mIHC data generated within the study.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488747.V1
Abstract: Inverse Simpson alpha ersity scores of the fecal microbiome by BMI in patients with metastatic melanoma stratified by sex. Box plot represents the median bar with the box bounding the IQR and whiskers the most extreme points within 1.5 x IQR. The red dots represent OW/OB patients and the blue dots represent NL patients by BMI. This is a subgroup analysis of Figure 5C.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627303
Abstract: Clinical and mIHC data generated within the study.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/1078-0432.CCR-17-2257
Abstract: Purpose: Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses, however, occur in less than half of those treated, and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate antitumor immune response. Patients and Methods: We performed multiparameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti–PD-1 therapy. Results: Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells were associated with improved melanoma-specific survival in immunotherapy-naïve melanoma patients. Local IL15 expression levels strongly correlated with these tumor-resident T-cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset, and these cells significantly expanded early during anti–PD-1 immunotherapy. Conclusions: Tumor-resident CD8+ T-cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti–PD-1 and anti–LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade. Clin Cancer Res 24(13) 3036–45. ©2018 AACR.
Publisher: Wiley
Date: 21-04-2019
DOI: 10.1111/HIS.13814
Abstract: Indoleamine 2,3-dioxygenase (IDO), an immunomodulatory enzyme, facilitates immune escape by tumours and promotes tumour progression. IDO inhibitors with and without additional anti-PD-1 therapy have been evaluated in recent and ongoing melanoma clinical trials, but IDO expression in melanoma tumours, and therefore its potential role as a predictive biomarker remains unknown. This study sought to evaluate IDO expression in immunotherapy-naive metastatic melanoma patients in order to determine patterns of expression in corresponding primary melanomas, locoregional metastases and distant metastases. Here, we evaluated IDO expression using immunohistochemistry in 99 melanoma tumour s les from 43 immunotherapy-naive patients with metastatic melanoma to determine patterns of expression in primary melanomas (n = 29), locoregional metastases (n = 36) and distant metastases (n = 34). Thirty-seven per cent of patients demonstrated tumour IDO expression in at least one specimen. Twelve of 35 patients (34%) with longitudinal specimens (i.e. two or more separate specimens from different disease stages in the same patient) displayed heterogeneous IDO staining between s les. Tumour IDO expression positively correlated with tumour-infiltrating lymphocyte (TIL) score as well as the number of IDO-expressing mononuclear cells in the primary melanoma (P < 0.0001 and P = 0.0011, respectively) and nodal metastases (P = 0.049 and P = 0.037, respectively), but not in distant metastases. Furthermore, tumour IDO expression correlated positively with PD-L1 expression by melanoma cells among all specimens (P = 0.0073). Therefore, while assessment of tumour IDO expression warrants evaluation in melanoma patient cohorts treated with IDO inhibitors dosed at levels proven to inhibit the target by pharmacodynamic assessment, its utility as a biomarker may be limited by intertumoral heterogeneity.
Publisher: American Association for Cancer Research (AACR)
Date: 04-0023
DOI: 10.1158/1078-0432.22488732.V1
Abstract: RNASeq data for the MDA cohort (n=61) with associated clinical info.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488744
Abstract: Differential gene expression analysis for covariates controlled.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488735
Abstract: Body mass index values by patient ID for all RNASeq cohorts.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2019
DOI: 10.1158/1078-0432.CCR-18-2795
Abstract: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity. The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids. Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51–0.84 P = 0.037] and 0.70 at EDT (95% CI, 0.55–0.85 P = 0.017) using ROC analysis. The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity. See related commentary by Johnson and Balko, p. 1452
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23627318.V1
Abstract: Cohort and dataset overview
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488738
Abstract: Differential gene expression analysis for each subgroup.
Publisher: BMJ
Date: 09-2022
Abstract: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases. We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV melanoma with a solitary site of organ metastasis. In an independent cohort we analyzed and compared immune cell densities, subpopulations and spatial distribution in tissue from liver, lung, brain, LN or subcut sites from 130 patients with stage IV melanoma. Patients with only liver, brain or bone metastases had shorter OS compared to those with lung, LN or subcutaneous and soft tissue metastases. Liver and brain metastases had significantly lower T-cell infiltration than lung (p=0.0116 and p=0.0252, respectively) and LN metastases (p=0.0116 and p=0.0252, respectively). T cells were further away from melanoma cells in liver than lung metastases (p=0.0335). Liver metastases displayed unique T-cell profiles, with a significantly lower proportion of programmed cell death protein-1+ T cells compared to all other anatomical sites (p .05), and a higher proportion of TIM-3+ T cells compared to LN (p=0.0004), subcut (p=0.0082) and brain (p=0.0128) metastases. Brain metastases had a lower macrophage density than subcut (p=0.0105), liver (p=0.0095) and lung (p .0001) metastases. Lung metastases had the highest proportion of programmed death ligand-1+ macrophages of the total macrophage population, significantly higher than brain (p .0001) and liver metastases (p=0.0392). Liver and brain melanoma metastases have a significantly reduced immune infiltrate than lung, subcut and LN metastases, which may account for poorer prognosis and reduced immunotherapy response rates in patients with liver or brain metastases. Increased TIM-3 expression in liver metastases suggests TIM-3 inhibitor therapy as a potential therapeutic opportunity to improve patient outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532803.V1
Abstract: AbstractPurpose: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Experimental Design: Associations between BMI [normal (NL 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts ( i n /i = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients ( i x /i = 36) by LC/MS, and in flow-sorted melanoma tumor cells ( i x /i = 37) and patient-derived melanoma cell lines ( i x /i = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort ( i n /i = 371). Results: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, ersity, and taxonomy of the fecal microbiome did not differ by BMI. Conclusions: These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-3028" target="_blank" See related commentary by Smalley, p. 5 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 27-09-2022
DOI: 10.1158/1078-0432.CCR-22-2661
Abstract: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Associations between BMI [normal (NL & 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371). DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, ersity, and taxonomy of the fecal microbiome did not differ by BMI. These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. See related commentary by Smalley, p. 5
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488729.V1
Abstract: Supplementary Table 1: Baseline characteristics for patients included in the integrated gene set enrichment analysis (Figure 2-3) by cohort Supplementary Table 6: The most frequent somatic alterations (alts) in patients with regionally metastatic melanoma by body mass index from The Cancer Genome Atlas cohort Supplemental Table 7: Integrated gene set enrichment analysis for pathways associated with fatty acid metabolism by body mass index Supplemental Table 8: Gene expression of selected genes of interest involved in fatty acid metabolism.
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2018
DOI: 10.1158/1078-0432.CCR-17-2267
Abstract: Immune checkpoint inhibitors have revolutionized the treatment of patients with advanced-stage metastatic melanoma, as well as patients with many other solid cancers, yielding long-lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed “acquired resistance”), whereas others do not respond at all (termed “primary resistance”). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma, and the known mechanisms underlying each involves various components of the cancer immune cycle, and interactions between multiple signaling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma and detail potential therapeutic strategies to prevent and overcome them. Clin Cancer Res 24(6) 1260–70. ©2017 AACR.
Publisher: Informa UK Limited
Date: 16-10-2020
No related grants have been discovered for Tuba Gide.