新辅助免疫疗法（NIT）在多种癌症中产生了临床效益。对NIT反应机制的特征化可能会导致治疗策略的改进。在这里，我们展示疲惫的肿瘤浸润CD8+T（Tex）细胞对同时新辅助TGF-β和PD-L1封锁显示出局部和系统性反应。NIT引起循环Tex细胞的显著和选择性增加，与肿瘤内组织保留标记CD103的表达降低相关。体外中和TGF-β后，CD8+T细胞上的TGF-β驱动的CD103表达被扭转，这表明TGF-β参与T细胞组织保留和受损系统免疫。转录改变表明T细胞受体信号和谷氨酰胺代谢是增强Tex治疗反应或减少反应的重要决定因素。我们的分析说明了体内对NIT的T细胞反应的生理和代谢变化，突出了免疫抑制、组织保留和系统抗肿瘤免疫之间的相互作用，并建议抗T细胞组织保留作为一种有前途的新辅助治疗策略。由Elsevier Inc发布。

Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8+ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8+ T cells is reversed following TGF-β neutralization in vitro, implicating TGF-β in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying T cell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of T cell tissue retention as a promising neoadjuvant treatment strategy.Published by Elsevier Inc.