Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy

Zhen Bian, Lei Shi, Koby Kidder, Ke Zen, Charlie Garnett-Benson and Yuan Liu ()
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Zhen Bian: Center of Diagnostics and Therapeutics, Georgia State University
Lei Shi: Center of Diagnostics and Therapeutics, Georgia State University
Koby Kidder: Program of Cancer and Immunology, Georgia State University
Ke Zen: Program of Cancer and Immunology, Georgia State University
Charlie Garnett-Benson: Program of Cancer and Immunology, Georgia State University
Yuan Liu: Center of Diagnostics and Therapeutics, Georgia State University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα-deficient macrophages activated by irradiated tumor-released DAMPs exhibit robust efficacy and orchestrate an anti-tumor response that controls late-stage tumors. Upon RT-mediated activation, intratumoral SIRPα-deficient macrophages acquire potent proinflammatory features and conduct immunogenic antigen presentation that confer a tumoricidal microenvironment highly infiltrated by tumor-specific cytotoxic T cells, NK cells and inflammatory neutrophils, but with limited immunosuppressive regulatory T cells, myeloid derived suppressor cells and post-radiation wound-healing. The results demonstrate that SIRPα is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRPα-deficient macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases.

Date: 2021
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DOI: 10.1038/s41467-021-23442-z

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