Gruber, Thomas; Kremenovic, Mirela; Sadozai, Hassan; Rombini, Nives; Baeriswyl, Lukas; Maibach, Fabienne; Modlin, Robert L; Gilliet, Michel; von Werdt, Diego; Hunger, Robert E.; Jafari, S. Morteza Seyed; Parisi, Giulia; Abril-Rodriguez, Gabriel; Ribas, Antoni; Schenk, Mirjam (2020). IL-32γ potentiates tumor immunity in melanoma. JCI insight, 5(18) JCI Insight 10.1172/jci.insight.138772
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138772.2-20200916090359-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (25MB) | Preview |
Myeloid cells orchestrate the antitumor immune response and influence the efficacy of immune checkpoint blockade (ICB) therapies. We and others have previously shown that IL-32 mediates DC differentiation and macrophage activation. Here, we demonstrate that IL-32 expression in human melanoma positively correlates with overall survival, response to ICB, and an immune-inflamed tumor microenvironment (TME) enriched in mature DC, M1 macrophages, and CD8+ T cells. Treatment of B16F10 murine melanomas with IL-32 increased the frequencies of activated, tumor-specific CD8+ T cells, leading to the induction of systemic tumor immunity. Our mechanistic in vivo studies revealed a potentially novel role of IL-32 in activating intratumoral DC and macrophages to act in concert to prime CD8+ T cells and recruit them into the TME through CCL5. Thereby, IL-32 treatment reduced tumor growth and rendered ICB-resistant B16F10 tumors responsive to anti-PD-1 therapy without toxicity. Furthermore, increased baseline IL-32 gene expression was associated with response to nivolumab and pembrolizumab in 2 independent cohorts of patients with melanoma, implying that IL-32 is a predictive biomarker for anti-PD-1 therapy. Collectively, this study suggests IL-32 as a potent adjuvant in immunotherapy to enhance the efficacy of ICB in patients with non-T cell-inflamed TME.
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