Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA.
Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27708, USA.
Nat Commun. 2020 Dec 17;11(1):6410. doi: 10.1038/s41467-020-19917-0.
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.
免疫疗法未能治愈大多数癌症患者。临床前研究表明，放疗与免疫疗法协同作用，促进放射诱导的抗肿瘤免疫。大多数临床前免疫治疗研究都利用移植肿瘤模型，这些模型高估了患者的反应。在这里，我们表明 PD-1 阻断和放疗可治愈移植肉瘤，但相同的治疗在自发肉瘤中失败，这些肉瘤表现出免疫编辑、新抗原表达减少和肿瘤特异性免疫耐受。我们从移植和原发性肿瘤中对肿瘤浸润免疫细胞进行了特征描述，揭示了它们在免疫景观上的显著差异。尽管放疗重塑了两种模型中的髓样细胞，但只有移植肿瘤富含活化的 CD8+T 细胞。原发性鼠肉瘤的免疫微环境与大多数人类肉瘤相似，而移植肉瘤与炎症反应最强烈的人类肉瘤相似。这些结果确定了与免疫系统共同进化的鼠肉瘤中的不同微环境，并表明具有与移植肿瘤相似的肉瘤免疫表型的患者可能最受益于 PD-1 阻断和放疗。
