RNA-seq of tumor infiltrating CD8+ T cells from WT and Drd5-deficiency mice

Tissue adaptation of T-memory cells involves the constitutive upregulation of CD69 and CD103 levels, which sustain the enhanced ability of Trm cells to establish in the tumor niche and become better suited for fighting tumors. The accumulation of tumor-infiltrating lymphocytes (TILs) expressing the Trm cell marker CD103 in solid cancer also favors longer survival and reduced disease progression. However, the exogenous signals controlling Trm cells differentiation are not fully understood. Here, with high throughput drug screening, we identified that the neurotransmitter dopamine modulated CD8+ T-cells into the CD103+ Trm-cell fate. DRD5 served as the major functional dopamine receptor on CD8+ T-cells and positively correlated with TRM cell population in murine syngeneic tumor xenografts and clinical human colon cancer samples. Upon DRD5 deficiency, CD8+ T-cells failed to accumulate in tissues, resulting in impaired TRM cell formation, reduced effector function, and uncontrolled disease progression. With bulk RNA sequencing (RNA-seq), we compared the transcriptional characteristics of CD8+ TILs from wild-type (WT) control and DRD5 deficiency group. Our results indicated that DRD5 played an important role not only in tuning the differentiation of CD69+ CD103+ Trm but also in regulating the functionality of Trm cells in tumor.