Abstract
Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.
Highlights
Immunotherapy fails to cure most cancer patients
We find that the immune microenvironment of primary tumors compositionally resembles the majority of human soft tissue sarcomas, which are often immunotherapy-resistant, while transplant tumors model only the most highly inflamed subset of human sarcomas, which are more likely to respond to programmed cell death-1 (PD-1) blockade[19]
But not primary, tumors are enriched for activated CD8+ T cells and PD-L1+ macrophages, which are present in human sarcomas that respond to PD-1 blockade[20,21]
Summary
Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Preclinical studies using transplanted tumor models demonstrate that focal RT can synergize with immune checkpoint inhibitors to generate systemic antitumor immune responses In these abscopal responses, RT acts as an in situ vaccine[2,3,4] to eliminate tumors outside of the radiation field in a T cell- and type I interferon-dependent manner[5,6,7]. But not primary, tumors are enriched for activated CD8+ T cells and PD-L1+ macrophages, which are present in human sarcomas that respond to PD-1 blockade[20,21] These results suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy
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