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

• Published in: Nature communications 2021-05, Vol.12 (1), p.3229-3229, Article 3229
• Main Authors: Bian, Zhen, Shi, Lei, Kidder, Koby, Zen, Ke, Garnett-Benson, Charlie, Liu, Yuan
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 14/63; 38/39; 59/5; 631/67/1059/485; 631/67/580; 692/4028/67/1059/485; Anticancer properties; Antigen presentation; Antigens; Cancer; Cell activation; Cell-mediated immunity; Cytotoxicity; Humanities and Social Sciences; Humoral immunity; Immunity; Immunogenicity; Immunoregulation; Inflammation; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Macrophages; Metastases; Microenvironments; multidisciplinary; Myeloid cells; Pancreas; Post-radiation; Radiation; Radiation therapy; Remission; Science; Science (multidisciplinary); SHPS-1 protein; Suppressor cells; Tumors; Wound healing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23442-z

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. Signal-regulatory protein α (SIRPα) 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 Sirpα-deficient mice, providing evidences that RT-activated Sirpα-deficient macrophages promote T-cell mediated anti-tumor immune responses.