ORCID Profile
0000-0002-5099-3368
Current Organisation
QIMR Berghofer Medical Research Institute
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Publisher: American Association for Cancer Research (AACR)
Date: 2020
DOI: 10.1158/2159-8290.CD-19-0569
Abstract: Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics. This article is highlighted in the In This Issue feature, p. 1
Publisher: Wiley
Date: 25-07-2019
DOI: 10.1111/APT.15425
Abstract: Faecal calprotectin decreases during exclusive enteral nutrition in children with active Crohn's disease. It is unknown how faecal calprotectin changes during food re‐introduction and the influence of maintenance enteral nutrition. To study changes to faecal calprotectin during exclusive enteral nutrition and at food reintroduction, and explore associations with maintenance enteral nutrition. Children with Crohn's disease were followed during exclusive enteral nutrition and during food‐reintroduction. Faecal calprotectin was measured before, at 33 and 54 days of exclusive enteral nutrition, and at 17, 52 and 72 days after food‐reintroduction. Maintenance enteral nutrition use was recorded with estimated weight food diaries. Data are presented with medians and Q1:Q3. Sixty‐six patients started exclusive enteral nutrition and 41 (62%) achieved clinical remission (weighted paediatric Crohn's disease activity index .5). Baseline faecal calprotectin (mg/kg) decreased after 4 and 8 weeks of exclusive enteral nutrition (Start: 1433 [Q1: 946, Q3: 1820] vs 33 days: 844 [314, 1438] vs 54 days: 453 [165, 1100] P .001). Within 17 days of food reintroduction, faecal calprotectin increased to 953 [Q1: 519, Q3: 1611] and by 52 days to 1094 [660, 1625] (both P .02). Fifteen of 41 (37%) children in remission used maintenance enteral nutrition (333 kcal or 18% of energy intake). At 17 days of food reintroduction, faecal calprotectin was lower in maintenance enteral nutrition users than non‐users (651 [Q1: 271, Q3: 1781] vs 1238 [749, 2102], P = .049) and correlated inversely with maintenance enteral nutrition volume (rho: −0.573, P = .041), kcals (rho: −0.584, P = .036) and % energy intake (rho: −0.649, P = .016). Maintenance enteral nutrition use was not associated with longer periods of remission ( P = .7). Faecal calprotectin at the end of exclusive enteral nutrition did not predict length of remission. The effect of exclusive enteral nutrition on faecal calprotectin is diminished early during food reintroduction. Maintenance enteral nutrition at ~18% of energy intake is associated with a lower faecal calprotectin at the early phase of food reintroduction but is ineffective in maintaining longer term remission.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-04-2022
DOI: 10.1126/SCITRANSLMED.ABJ9779
Abstract: Neoadjuvant immunotherapy with anti-cytotoxic T lymphocyte–associated protein 4 (CTLA4) + anti–programmed cell death protein 1 (PD1) monoclonal antibodies has demonstrated remarkable pathological responses and relapse-free survival in ~80% of patients with clinically detectable stage III melanoma. However, about 20% of the treated patients do not respond. In pretreatment biopsies of patients with melanoma, we found that resistance to neoadjuvant CTLA4 + PD1 blockade was associated with a low CD4/interleukin-2 (IL-2) gene signature. Ex vivo, addition of IL-2 to CTLA4 + PD1 blockade induced T cell activation and deep immunological responses in anti-CTLA4 + anti-PD1–resistant human tumor specimens. In the 4T1.2 breast cancer mouse model of neoadjuvant immunotherapy, triple combination of anti-CTLA4 + anti-PD1 + IL-2 cured almost twice as many mice as compared with dual checkpoint inhibitor therapy. This improved efficacy was due to the expansion of tumor-specific CD8 + T cells and improved proinflammatory cytokine polyfunctionality of both CD4 + and CD8 + T effector cells and regulatory T cells. Depletion studies suggested that CD4 + T cells were critical for priming of CD8 + T cell immunity against 4T1.2 and helped in the expansion of tumor-specific CD8 + T cells early after neoadjuvant triple immunotherapy. Our results suggest that the addition of IL-2 can overcome resistance to neoadjuvant anti-CTLA4 + anti-PD1, providing the rationale for testing this combination as a neoadjuvant therapy in patients with early-stage cancer.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2015
DOI: 10.1038/LEU.2015.71
Abstract: High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 05-09-2014
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22535711.V1
Abstract: Supplementary text and figures
Publisher: Oxford University Press (OUP)
Date: 17-07-2019
DOI: 10.1111/BJD.18008
Abstract: Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8 To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression. Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2020
DOI: 10.1158/1078-0432.CCR-19-3925
Abstract: Resistance to anti-PD1–based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB. Pretreatment tumor specimens, from 155 patients with metastatic melanoma treated with ICB and from 50 patients treated with BRAF/MEK-directed targeted therapy, were assessed for CD155 expression by IHC. Intratumor T-cell features were analyzed using multiplex-immunohistofluorescence for CD8, PD1, and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA sequencing results, as well as clinical RECIST response and progression-free survival. High pretreatment CD155 tumor levels correlated with high parenchymal PD1+CD8+/CD8+ T-cell ratios (PD1tR) and poor response to anti-PD1 therapy. In PDL1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/CTLA4 therapy. Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1+CD8+ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for patients with metastatic melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22535711
Abstract: Supplementary text and figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6547925.V1
Abstract: Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells i in vivo /i in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in i Mr1 /i sup −/− /sup mice, compared with wild-type mice. The antitumor activity observed in i Mr1 /i sup −/− /sup mice required natural killer (NK) and/or CD8 sup + /sup T cells and IFNγ. Adoptive transfer of MAIT cells into i Mr1 /i sup −/− /sup mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy. Significance: Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics. i This article is highlighted in the In This Issue feature, p. 1 /i /
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Elizabeth McDonald.