Tissue-resident memory CD8+ T (TRM) cells have been associated with robust protective antitumor immune responses and improved prognosis of patients with cancer. Therefore, therapeutic strategies that modulate either the production or activity of TRM cells could be effective for treating cancer. Using a high-throughput drug screen, we showed that the neurotransmitter dopamine drives differentiation of CD8+ T cells into CD103+ TRM cells. In murine syngeneic tumor xenograft models and clinical human colon cancer samples, DRD5 served as the major functional dopamine receptor on CD8+ T cells and positively correlated with TRM cell density. DRD5 deficiency led to a failure of CD8+ T cells to accumulate in tissues, resulting in impaired TRM cell formation, reduced effector function, and uncontrolled disease progression. Moreover, dopamine treatment promoted the antitumor activity of CD8+ T cells and suppressed colorectal cancer growth in immunocompentent mouse models, and ex vivo preconditioning with dopamine enhanced the in vivo efficacy of chimeric antigen receptor (CAR)-T cells. Finally, in a patient with colorectal cancer cohort, dopamine expression was positively associated with patient survival and CD8+ T-cell infiltration. These findings suggest that dopaminergic immunoregulation plays an important role in the differentiation of CD8+ cells into CD103+ TRM cells and thereby modulates TRM-elicited antitumor immunity in colorectal cancer. Significance: Identification of an immunostimulatory function of dopamine signaling by promoting tissue-resident memory T-cell differentiation and sustaining T-cell effector functions reveals potential therapeutic strategies and prognostic biomarkers for colorectal cancer.

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多巴胺信号传导促进 CD8+ T 细胞的组织驻留记忆分化和抗肿瘤免疫

组织驻留记忆 CD8+ T (TRM) 细胞与强大的保护性抗肿瘤免疫反应和改善癌症患者的预后相关。因此，调节 TRM 细胞的产生或活性的治疗策略可能有效治疗癌症。使用高通量药物筛选，我们发现神经递质多巴胺驱动 CD8+ T 细胞分化为 CD103+ TRM 细胞。在小鼠同基因肿瘤异种移植模型和临床人类结肠癌样本中，DRD5 是 CD8+ T 细胞上的主要功能性多巴胺受体，并与 TRM 细胞密度呈正相关。DRD5 缺陷导致 CD8+ T 细胞无法在组织中积累，从而导致 TRM 细胞形成受损、效应功能降低和疾病进展失控。而且，在免疫功能正常的小鼠模型中，多巴胺治疗可促进 CD8+ T 细胞的抗肿瘤活性并抑制结直肠癌的生长，而多巴胺的离体预处理可增强嵌合抗原受体 (CAR)-T 细胞的体内功效。最后，在结直肠癌患者中，多巴胺表达与患者生存和 CD8+ T 细胞浸润呈正相关。这些发现表明，多巴胺能免疫调节在 CD8+ 细胞分化为 CD103+ TRM 细胞中发挥重要作用，从而调节 TRM 引发的结直肠癌抗肿瘤免疫。意义：