The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Clinical/Translational Section Editor, Dr. Claudia Palena.
“Transcriptomic Determinants of Response to Pembrolizumab Monotherapy across Solid Tumor Types” by Razvan Cristescu et al Clin Cancer Res (2022)A number of transcriptomic signatures have been put forward to predict response or lack thereof to checkpoint blockade. Using RNA-sequencing data from the tumor tissue of 1,188 patients who received pembrolizumab monotherapy on clinical trials across seven tumor types, Razvan Critescu and colleagues performed a prospectively specified retrospective analysis of the relationship between 11 unique gene expression signatures and clinical response. In a rigorous statistical approach, associations were adjusted for tumor type, ECOG performance status, and the similarity of each signature to the T-cell-inflamed gene expression profile, which was previously validated to predict response to pembrolizumab. The additional 10 consensus RNA expression signatures beyond T cell inflamed gene expression profile were developed from RNA coexpression patterns in the Merck–Moffitt and The Cancer Genome Atlas databases reflective of canonical tumor biology and tumor microenvironment-associated pathways. There was minimal overlap of included genes between signature panels, which ranged in size from 11 to 227 loci. Predictably, the 18-gene T cell inflamed gene expression profile demonstrated the strongest association with a positive response to pembrolizumab, with angiogenesis, myeloid-derived suppressor cell, and stroma/epithelial-to-mesenchymal transition/transforming growth factor beta signatures demonstrating a significant (p < 0.05) but more modest (AUROC < 0.6) negative association with response. None of the signatures were truly universal, some had improved predictive power in triple-negative breast cancer or head and neck squamous cell carcinoma and less predictive value for melanoma, gastric cancer, or renal cell carcinoma. Why this matters: This rigorous, prespecified analysis identifies novel gene signatures of non-interferon gamma-related elements of the tumor microenvironment that independently predict resistance to anti-PD-1 monotherapy. With further development, these gene signatures may assist in patient selection for immunotherapy or provide targets for therapeutic development.“Androgen receptor activity in T cells limits checkpoint blockade efficacy” by Xiangnan Guan et al
Nature (2022)To date, anti-PD-(L)1 immune checkpoint inhibitors have not yielded responses in metastatic castration-resistant prostate cancer (mCRPC), however, the mechanisms of primary resistance remain poorly understood. Xiangnan Guan and colleagues revealed novel immunosuppressive effects of androgen receptor signaling in prostate cancer, potentially opening the door to combination approaches involving androgen deprivation therapy (ADT) and checkpoint blockade. Analyses of immune cell infiltrates from eight metastatic lesions in patients who had disease progression on enzalutamide and were subsequently treated with anti-PD-1 revealed a downregulation in androgen receptor signaling in CD8+ T cells from the three tumors that responded compared to the five non-responding tumors. In mouse models, the combination of surgical ADT followed by anti-PD-L1 and enzalutamide reduced tumor growth and improved survival compared to the respective monotherapies. The immune response from the surgery plus combination therapy was characterized by increased abundance of infiltrating CD8+ T cells, enhanced cytotoxic effector function via increased expression of granzyme B, interferon gamma, and tumor necrosis factor, and downregulation of androgen receptor signaling. Androgen receptor binding on open chromatin regions near the interferon gamma and granzyme B loci in T cells was reduced by enzalutamide treatment. Loss of androgen receptor signaling also protected CD8+ T cells from exhaustion and loss of interferon gamma production. In two independent melanoma datasets, androgen receptor signaling negatively correlates with CD8+ T cell response signatures and interferon gamma production. Why this matters: Taken together, the data delineate an androgen receptor-mediated mechanism of immunosuppression in mCRPC that may be reversed by combination ADT and anti-PD-L1. These findings lay the groundwork for investigation of combination of ADT plus anti-PD-(L)1 to overcome primary immunotherapy resistance in patients with mCRPC and potentially other types of solid tumors as well. “Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity” by Yared Hailemichael et alCancer Cell (2022)While immune checkpoint inhibitors (ICIs) offer deep and durable responses for many cancers, severe immune-related adverse events (irAEs) and resistance are obstacles to maximal clinical benefit for patients. Previously, increased serum levels of interleukin (IL)-6 have been associated with irAE development, leading to Yared Hailemichael and colleagues to investigate the consequences of IL-6 blockade on ICI anti-tumor activity and incidence of irAEs. Increased IL-6 and a Th17 expression signature was seen in 23 biopsy samples of immune-related enterocolitis tissue compared to patient-matched normal tissue. Higher IL-6 expression was also observed in non-responding tumors compared to patient-matched tumors that responded to ICI therapy. In murine melanoma and colorectal cancer models, IL-6 blockade combined with anti-CTLA-4 resulted in a lower tumor burden compared to anti-CTLA-4 treatment alone. Mechanistically, the anti-IL-6/anti-CTLA-4 combination was associated with increased effector and antigen-specific tumor infiltrating lymphocytes and decreased myeloid suppressor cells compared to either monotherapy. In an experimental autoimmune encephalitis model used, the addition of IL-6 blockade to anti-CTLA-4 treatment significantly reduced severity of the autoimmune disease with no loss of anti-tumor efficacy. Retrospective analyses of patients who had irAEs managed with the anti-IL-6 tocilizumab found no reduction in objective response rates after intervention. A phase II, investigator-initiated clinical trial is planned (NCT04940299) to assess safety and efficacy of tocilizumab in combination with ipilimumab and nivolumab for treatment-naïve metastatic melanoma, non-small cell lung cancer, and urothelial carcinoma. Why this matters: This study provides the preclinical foundation for future human trials evaluating anti-IL-6 agents to reduce irAEs and enhance anti-tumor immune responses with ICIs.“Spatially mapping the immune landscape of melanoma using imaging mass cytometry” by Dan Moldoveanu et al Sci Immunol (2022)Melanoma is an immunologically hot tumor that often responds to immunotherapy, but the relationships between tumor, immune, and stromal cells that lead to anti-tumor immunity remain poorly understood. To characterize how spatial relationships between immune and melanoma cells in the tumor microenvironment determine clinical response to checkpoint blockade, Dan Moldoveanu et al used cytometry time-of-flight imaging mass cytometry with a panel of 35 antibodies recognizing immune cells (CD3, CD4, CD8, CD20, CD68, CD45RO), checkpoints (CD40, ICOS, VISTA, LAG3, TIM3, PD-L1, OX40), melanoma cells (SOX10, S100) and regulators (beta-catenin, ERK, MEK), stromal cells (CD31), and proliferation (Ki67). Analysis of samples from 5 benign and 67 malignant melanomas revealed globally significantly more macrophages/monocytes and cytotoxic/helper T cells compared to B and regulatory T cells. A higher proportion of Ki67+ antigen-experienced cytotoxic T cells was associated with an improved response to ICI therapy (p = 0.022) and improved survival (p = 0.0019). Whole slide immunofluorescence microscopy in a validation cohort of 25 cutaneous melanoma samples demonstrated similar trends towards improved survival with ICIs for patients with higher proportions of proliferating cytotoxic antigen-experienced T cells. Closer pre-treatment proximity or higher amounts of direct contact between antigen-experienced T cells and melanoma were significantly associated with response to ICIs. These associations persisted when controlling for cell type proportions and tumor structure.Why this matters: This study offers rich insight into the melanoma tumor microenvironment and reveals a new correlate of response to checkpoint blockade. Future characterizations of the proximity and contact frequency of infiltrating lymphocytes and tumor cells measured by multiplexed techniques may assist in patient selection for immunotherapy.
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