CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1⁺ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1⁺ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6⁺ TCF1⁺ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6⁺ TCF1⁺ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

CD8 T 细胞针对不同肿瘤新抗原的反应同时发生，但对于反应之间的相互作用及其对 T 细胞功能和肿瘤控制的影响知之甚少。在小鼠肺腺癌中，我们发现肿瘤中建立了免疫优势，其中 CD8 T 细胞扩增主要由最稳定地结合 MHC 的抗原驱动。对次优势抗原做出反应的 T 细胞富集了与免疫检查点阻断 (ICB) 治疗反应相关的 TCF1 ⁺祖细胞表型。然而，由于以 CCR6 和 Tc17 分化为标志的 TCF1 ⁺细胞亚群功能失调，次优势 T 细胞反应并未优先受益于 ICB。对人类样本和测序数据集的分析表明，CCR6 ⁺ TCF1 ⁺细胞存在于人类癌症中，并且与 ICB 反应不相关。疫苗接种消除了 CCR6 ⁺ TCF1 ⁺细胞并显着改善了次优势反应，突出了最佳地同时针对肿瘤产生新抗原反应的策略。