Sir Peter MacCallum Department of Oncology - Research Publications
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ItemChallenges of PD-L1 testing in non-small cell lung cancer and beyond(AME PUBLISHING COMPANY, 2020-08)
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ItemNo Preview AvailableBlockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma(NATURE PORTFOLIO, 2021-07)Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
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ItemTherapeutic strategies to remodel immunologically cold tumors(WILEY, 2020)Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these 'responsive' tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near-complete absence of lymphocytes from the tumor, so-called immunologically cold tumors. Here, we propose two broad approaches to convert 'cold' tumors into 'hot' tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor-beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen-presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort.
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ItemHigh-dimensional analyses reveal a distinct role of T-cell subsets in the immune microenvironment of gastric cancer(WILEY, 2020-05)OBJECTIVES: To facilitate disease prognosis and improve precise immunotherapy of gastric cancer (GC) patients, a comprehensive study integrating immune cellular and molecular analyses on tumor tissues and peripheral blood was performed. METHODS: The association of GC patients' outcomes and the immune context of their tumors was explored using multiplex immunohistochemistry (mIHC) and transcriptome profiling. Potential immune dysfunction mechanism/s in the tumors on the systemic level was further examined using mass cytometry (CyTOF) in complementary peripheral blood from selected patients. GC cohorts with mIHC and gene expression profiling data were also used as validation cohorts. RESULTS: Increased CD4+FOXP3+ T-cell density in the GC tumor correlated with prolonged survival. Interestingly, CD4+FOXP3+ T cells had a close interaction with CD8+ T cells rather than tumor cells. High densities of CD4+FOXP3+ T cells and CD8+ T cells (High-High) independently predicted prolonged patient survival. Furthermore, the interferon-gamma (IFN-γ) gene signature and PDL1 expression were up-regulated in this group. Importantly, a subgroup of genomically stable (GS) tumors and tumors with chromosomal instability (CIN) within this High-High group also had excellent survival. The High-High GS/CIN tumors were coupled with increased frequencies of Tbet+CD4+ T cells and central memory CD4+ T cells in the peripheral blood. CONCLUSION: These novel findings identify the combination of CD8+ T cells and FOXP3+CD4+ T cells as a significant prognostic marker for GC patients, which also could potentially be targeted and applied in the combination therapy with immune checkpoint blockades in precision medicine.
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ItemHigh dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot(BMJ PUBLISHING GROUP, 2020)BACKGROUND: Prostate cancer (PCa) has a profoundly immunosuppressive microenvironment and is commonly immune excluded with few infiltrative lymphocytes and low levels of immune activation. High-dose radiation has been demonstrated to stimulate the immune system in various human solid tumors. We hypothesized that localized radiation therapy, in the form of high dose-rate brachytherapy (HDRBT), would overcome immune suppression in PCa. METHODS: To investigate whether HDRBT altered prostate immune context, we analyzed preradiation versus postradiation human tissue from a cohort of 24 patients with localized PCa that received HDRBT as primary treatment (RadBank cohort). We performed Nanostring immune gene expression profiling, digital spatial profiling, and high-throughput immune cell multiplex immunohistochemistry analysis. We also resolved tumor and nontumor zones in spatial and bioinformatic analyses to explore the immunological response. RESULTS: Nanostring immune profiling revealed numerous immune checkpoint molecules (eg, B7-H3, CTLA4, PDL1, and PDL2) and TGFβ levels were increased in response to HDRBT. We used a published 16-gene tumor inflammation signature (TIS) to divide tumors into distinct immune activation states (high:hot, intermediate and low:cold) and showed that most localized PCa are cold tumors pre-HDRBT. Crucially, HDRBT converted 80% of these 'cold'-phenotype tumors into an 'intermediate' or 'hot' class. We used digital spatial profiling to show these HDRBT-induced changes in prostate TIS scores were derived from the nontumor regions. Furthermore, these changes in TIS were also associated with pervasive changes in immune cell density and spatial relationships-in particular, between T cell subsets and antigen presenting cells. We identified an increased density of CD4+ FOXP3+ T cells, CD68+ macrophages and CD68+ CD11c+ dendritic cells in response to HDRBT. The only subset change specific to tumor zones was PDL1- macrophages. While these immune responses were heterogeneous, HDRBT induced significant changes in immune cell associations, including a gained T cell and HMWCK+ PDL1+ interaction in tumor zones. CONCLUSION: In conclusion, we showed HDRBT converted "cold" prostate tumors into more immunologically activated "hot" tissues, with accompanying spatially organized immune infiltrates and signaling changes. Understanding and potentially harnessing these changes will have widespread implications for the future treatment of localized PCa, including rational use of combination radio-immunotherapy.