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Published on: August 9, 2019
Dopamine Signaling Promotes Tissue-Resident Memory Differentiation of CD8+ T Cells and Antitumor Immunity
Yingshi Chen1, Shu-Mei Yan1,2, Zeyu Pu1
1Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
Abstract:
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.
Insights
Dopamine promotes the development of tissue-resident memory CD8+ T cells (TRM) via the DRD5 receptor, enhancing antitumor immunity in colorectal cancer. This discovery offers potential therapeutic strategies and prognostic biomarkers for cancer treatment.
Area of Science:
- Immunology
- Neuroscience
- Oncology
Background:
- Tissue-resident memory CD8+ T (TRM) cells are crucial for effective antitumor immune responses and patient prognosis in cancer.
- Therapeutic strategies targeting TRM cell production or activity hold promise for cancer treatment.
Purpose of the Study:
- To investigate the role of dopamine in regulating CD8+ T cell differentiation into TRM cells.
- To identify the dopamine receptor involved in this process and its therapeutic implications for colorectal cancer.
Main Methods:
- High-throughput drug screening to identify modulators of TRM cell differentiation.
- Utilized murine syngeneic tumor xenograft models and human colon cancer samples.
- Investigated the function of the dopamine receptor DRD5 on CD8+ T cells.
- Assessed the impact of dopamine treatment and DRD5 deficiency on antitumor immunity and cancer progression.
- Analyzed a patient cohort to correlate dopamine expression with survival and T-cell infiltration.
Main Results:
- Dopamine was identified as a key driver of CD8+ T cell differentiation into CD103+ TRM cells.
- DRD5 was confirmed as the primary functional dopamine receptor on CD8+ T cells, correlating positively with TRM cell density.
- DRD5 deficiency impaired TRM cell formation, reduced effector function, and led to uncontrolled tumor progression.
- Dopamine treatment enhanced CD8+ T cell antitumor activity and suppressed colorectal cancer growth in mice.
- Ex vivo dopamine preconditioning improved the efficacy of CAR-T cells.
- In patients, dopamine expression correlated with improved survival and increased CD8+ T-cell infiltration.
Conclusions:
- Dopaminergic signaling is essential for CD8+ T cell differentiation into CD103+ TRM cells.
- Dopamine acts as an immunostimulatory molecule, enhancing antitumor immunity in colorectal cancer.
- DRD5 is a potential therapeutic target and prognostic biomarker for colorectal cancer, suggesting novel avenues for cancer immunotherapy.
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