IL-32γ potentiates tumor immunity in melanoma

• Published in: JCI insight 2020-09, Vol.5 (18)
• Main Authors: Gruber, Thomas, Kremenovic, Mirela, Sadozai, Hassan, Rombini, Nives, Baeriswyl, Lukas, Maibach, Fabienne, Modlin, Robert L, Gilliet, Michel, von Werdt, Diego, Hunger, Robert E, Seyed Jafari, S Morteza, Parisi, Giulia, Abril-Rodriguez, Gabriel, Ribas, Antoni, Schenk, Mirjam
• Format: Article
• Language: English
• Subjects: Immunology; Oncology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.138772

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.