Dopamine Signaling Promotes Tissue-Resident Memory Differentiation of CD8(+) T Cells and Antitumor Immunity

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.