IL-32γ potentiates tumor immunity in melanoma

JCI Insight. 2020 Sep 17;5(18):e138772. 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.

Keywords: Cancer immunotherapy; Cellular immune response; Immunology; Melanoma; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Proliferation
  • Cohort Studies
  • Dendritic Cells / immunology
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Lymphocytes / immunology
  • Macrophages / immunology
  • Male
  • Melanoma / drug therapy
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nivolumab / administration & dosage
  • Prognosis
  • Survival Rate
  • Tumor Cells, Cultured
  • Tumor Microenvironment / immunology*
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • IL32 protein, human
  • Interleukins
  • Nivolumab
  • pembrolizumab