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

Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRP alpha 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. SIRP alpha (-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 SIRP alpha (-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 SIRP alpha is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRP alpha (-deficient) macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases. Signal-regulatory protein alpha (SIRP alpha) is an inhibitory receptor expressed by myeloid cells. Here the authors show that, in preclinical cancer models, resistance to radiotherapy (RT) observed in wild-type mice is overcome in Sirp alpha -deficient mice, providing evidences that RT-activated Sirp alpha -deficient macrophages promote T-cell mediated anti-tumor immune responses.