Journal Article
. 2021 Mar; 206(8):1966-1975.
doi: 10.4049/jimmunol.2000523.

IL-1α Mediates Innate and Acquired Resistance to Immunotherapy in Melanoma

Shubhra Singh 1 Zhilan Xiao 2 Karishma Bavisi 1 Jason Roszik 2 Brenda D Melendez 3 Zhiqiang Wang 4 Mark J Cantwell 5 Richard E Davis 1 Greg Lizee 2 Patrick Hwu 2 Sattva S Neelapu 1 Willem W Overwijk 6 Manisha Singh 7 
Affiliations
  • PMID: 33722878
  •     36 References
  •     3 citations

Abstract

Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.

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