Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA.
Commun Biol. 2020 Jul 8;3(1):355. doi: 10.1038/s42003-020-1083-1.
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.
内源性抗肿瘤反应受到限制的部分原因是缺乏肿瘤反应性 T 细胞，这是胸腺中枢耐受机制确保预防自身免疫的必然结果。在这里，我们表明，在缺乏 Aire 的小鼠中，免疫检查点阻断诱导的肿瘤排斥反应显著增强，这是中枢耐受破坏的典型表现。观察到的肿瘤排斥反应协同作用扩展到不同的肿瘤模型，伴随着高水平表达 Gzma、Gzmb、穿孔素、Cxcr3 的激活 T 细胞数量增加，以及与野生型小鼠相比，肿瘤内 Cxcl9 和 Cxcl10 的水平增加。与 Aire 在 T 细胞 repertoire 选择中的中枢作用一致，单细胞 TCR 测序揭示了具有高肿瘤反应性的几个克隆的扩增。这些数据表明，中枢耐受的破坏与免疫检查点阻断协同作用，增强了抗肿瘤免疫，并且可以作为一个模型来揭示新的抗肿瘤疗法，包括抗肿瘤 TCR，通常在中枢耐受过程中被清除。
