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 underestimate 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 immunogenicity, decreased neoadjuvant 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 rare 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.

Amy J. Wisdom, Yvonne M. Mowery, Cierra S. Hong, Jonathon E. Himes, Barzin Y. Nabet, Xiaodi Qin, Dadong Zhang, Lan Chen, Hélène Fradin, Rutul Kumar Patel, Alex M. Bassil, Eric S. Miuse, Daniel A. King, Eric S. Xuo, David J. Carpenter, Collin L. Kent, Kimberly S. Smythe, Nerissa T. Williams, Lixia Luo, Yan Ma, Ash A. Alizadeh, Kouros Owzar, Maximilian Diehn, Todd Bradley, David G. Kirsch