Dopamine Signaling Promotes Tissue-Resident Memory Differentiation of CD8+ T Cells and Antitumor Immunity
Dopamine Signaling Promotes Tissue-Resident Memory Differentiation of CD8+ T Cells and Antitumor Immunity
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DOI：
10.1158/0008-5472.can-21-4084
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发表时间：
2022-09-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Yiwen
中科院分区：
文献类型：
--
作者：
Chen, Yingshi;Yan, Shu-Mei;Zhang, Yiwen
组织驻留记忆性CD 8（+）T（TRM）细胞与强大的抗肿瘤免疫保护反应和改善癌症患者的预后有关。因此，调节TRM细胞的产生或活性的治疗策略可能对治疗癌症有效。使用高通量药物筛选，我们发现神经递质多巴胺驱动CD 8（+）T细胞分化为CD 103（+）N; TRM细胞。在鼠同基因肿瘤异种移植物模型和临床人结肠癌样品中，DRD 5充当CD 8和PLUSMN; T细胞上的主要功能性多巴胺受体，并且与TRM细胞密度正相关。DRD 5缺陷导致CD 8（+）T细胞无法在组织中积累，导致TRM细胞形成受损，效应子功能降低和疾病进展失控。此外，多巴胺治疗促进了CD 8（+）T细胞的抗肿瘤活性并抑制了免疫活性小鼠模型中结直肠癌的生长，并且多巴胺离体预处理增强了嵌合抗原受体（CAR）-T细胞的体内功效。最后，在结直肠癌患者队列中，多巴胺表达与患者生存率和CD 8（+）T细胞浸润呈正相关。这些结果表明多巴胺能免疫调节因子在CD 8（+）细胞向CD 103（+）TRM细胞分化中起重要作用，并由此调节TRM诱导的结直肠癌抗肿瘤免疫。重要性：通过促进组织驻留记忆T细胞分化和维持T细胞效应器功能来鉴定多巴胺信号传导的免疫刺激功能揭示了结直肠癌的潜在治疗策略和预后生物标志物。
Tissue-resident memory CD8(+)T (TRM) cells have been asso-ciated with robust protective antitumor immune responses and improved prognosis of patients with cancer. Therefore, thera-peutic 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(+)N; TRM cells. In murine syngeneic tumor xenograft models and clinical human colon cancer samples, DRD5 served as the major functional dopamine receptor on CD8 & PLUSMN; 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 posi-tively associated with patient survival and CD8(+)T-cell infiltra-tion. These findings suggest that dopaminergic immunoregula-ti on 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.