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

Autor:	Singh S; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Xiao Z; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Bavisi K; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Roszik J; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Melendez BD; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Wang Z; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Cantwell MJ; Memgen, Inc., Houston, TX 77046; and., Davis RE; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Lizee G; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Hwu P; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Neelapu SS; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77054., Overwijk WW; Nektar Therapeutics, San Francisco, CA 94158., Singh M; Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77054; msingh4@mdanderson.org.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2021 Apr 15; Vol. 206 (8), pp. 1966-1975. Date of Electronic Publication: 2021 Mar 15.
DOI:	10.4049/jimmunol.2000523
Abstrakt:	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. (Copyright © 2021 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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