Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade

免疫系统 CD8型 肿瘤微环境 癌症研究 免疫检查点 细胞毒性T细胞 T细胞 免疫学 生物 免疫疗法 医学 体外 生物化学
作者
Justin C. Jagodinsky,Jessica M. Vera,Won Jong Jin,Amanda G. Shea,Paul A. Clark,Raghava N. Sriramaneni,Thomas C. Havighurst,Ishan Chakravarthy,Raad H. Allawi,KyungMann Kim,Paul M. Harari,Paul M. Sondel,Michael A. Newton,Marka R. Crittenden,Michael J. Gough,Jessica R. Miller,Irene M. Ong,Zachary S. Morris
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:16 (765)
标识
DOI:10.1126/scitranslmed.adk0642
摘要

Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.
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