Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines.

中文翻译：

---

引流淋巴结中的预处理肿瘤新抗原反应并不常见，但可以预测检查点阻断治疗的结果。

免疫检查点阻断 (ICPB) 在某些患者中是一种非常有效的癌症疗法。肿瘤新抗原可能是攻击的主要目标，但尚不清楚个体癌症中哪些和多少肿瘤突变实际上是抗原性的，无论是否使用 ICPB 治疗，以及它们作为新抗原疫苗或作为 ICPB 反应预测因子的作用。为了检验这一点，我们在小鼠模型中询问了对肿瘤新抗原的免疫反应，其中肿瘤由天然人类致癌物（即石棉）诱导并模仿其人类对应物（即间皮瘤）。我们鉴定并筛选了 33 种候选新抗原，并发现 T 细胞对荷瘤动物中的一种候选新抗原（突变体 UQCRC2）产生反应。有趣的是，我们发现在其他方面相同的小鼠中，新抗原反应的幅度存在高度的动物间差异。使用细胞毒性 T 淋巴细胞相关蛋白 (CTLA-4) 和 α-糖皮质激素诱导的 TNFR 家族相关基因 (GITR) 进行 ICPB 治疗，其剂量可诱导肿瘤消退、增加反应幅度并揭示针对另一种新肿瘤的功能性 T 细胞反应。抗原，UNC45a。重要的是，治疗前引流淋巴结 (dLN) 对 UNC45a 的反应程度与 ICPB 治疗结果密切相关。然而，令人惊讶的是，提高预处理 UNC45a 特异性 T 细胞数量并没有提高对 ICPB 的反应率。这些观察结果表明一种新的生物标志物方法可用于临床预测 ICPB 反应，并对新抗原疫苗的开发具有重要意义。