The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire’s central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance.

内源性抗肿瘤反应部分受到肿瘤反应性 T 细胞缺乏的限制，这是确保预防自身免疫的胸腺中枢耐受机制的必然结果。在这里，我们发现，在艾尔缺陷小鼠中，免疫检查点阻断诱导的肿瘤排斥显着增强，这是中枢耐受破坏的缩影。与野生型小鼠相比，观察到的肿瘤排斥协同作用扩展到不同的肿瘤模型，伴随着表达高水平 Gzma、Gzmb、穿孔素、Cxcr3 的活化 T 细胞数量增加，以及 Cxcl9 和 Cxcl10 肿瘤内水平增加。与 Aire 在 T 细胞库选择中的核心作用一致，单细胞 TCR 测序揭示了几个具有高肿瘤反应性的克隆的扩增。数据表明，中枢耐受的破坏与免疫检查点阻断在增强抗肿瘤免疫力方面具有协同作用，并且可以作为揭示新型抗肿瘤疗法的模型，包括抗肿瘤TCR，这些疗法通常在中枢耐受期间被清除。