Serotonin receptor HTR2B signalling modulates adaptive immune response to colon cancer and metastasis 2258790

Abstract

Abstract Introduction Neuro-immune communication is essential for body regulation in both health and disease. Serotonin, a neurotransmitter, influences the functions of immune cells and promotes the growth of cancer. The specific roles of serotonin receptors in immune responses and cancer progression are still unclear. Methods An orthotopic colon tumor model was developed in C57BL/6 mice by injecting the colon tumor cell line, MC38 cells. Spectral flow cytometry, multicolor immunohistological analysis, and quantitative real-time PCR (qRT-PCR) were used. Results Our analysis of TCGA colon cancer patients’ data (n = 220) revealed a significant negative correlation between HTR2B expression in tumor tissue and patient survival. Colon cancer tissue biopsies showed higher levels of HTR2B and tryptophan hydroxylase (an enzyme required for serotonin synthesis) than those in healthy tissues. Treatment of tumor-bearing mice with the HTR2B-specific agonist BW-723C86 promoted tumor growth, whereas the specific antagonist RS-127445 significantly reduced colon tumor growth and metastasis. Tumor-induced using MC38-expressing ovalbumen showed that HTR2B antagonism promotes ova-antigen-specific effector CD8 T cell response. Furthermore, HTR2B agonism in mice promoted the serum circulation of PD-L1 molecules, which were significantly reduced with the HTR2B antagonist. HTR2B-antagonist treatment enhanced CD8 T cell function by decreasing the expression of checkpoint molecules (CTLA-4, PD-1, TIM-3) and inhibiting Foxp3+ Tregs in the tumor. Combining a low-dose HTR2B Antagonist with minimal doses of checkpoint inhibitors (anti-PD1, anti-PD-L1, or anti-CTLA4 mAb) or chemotherapeutic agents resulted in significantly reduced tumor growth. Conclusion We demonstrate that colon tumors exhibit altered HTR2B expression, and targeting HTR2B promotes antigen-specific anti-tumor immunity. These results suggest that the neuro-immune axis of HTR2B signaling forms a promising therapeutic strategy for controlling tumor growth and metastasis. Funding Source GL received a Swarna Jayanti Fellowship (DST/SJF/LSA-01/2017-2018) from the Department of Science and Technology, a TATA Innovation Fellowship (HRD-16012/5/2024) from the Department of Biotechnology, and a research grant from the Science and Engineering Research Board (CRG/2022/007108), Ministry of Science and Technology, Government of India. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)