Tu202 - CHRM4 Promotes Immunosuppressive Response in the Tumor Microenvironment to Promote Neuroendocrine Differentiation of Prostate Cancer

Wei-Yu Chen – Department of Pathology – Taipei Medical University; Hsiu-Lien Yeh – College of Medical Science and Technology – Taipei Medical University; Yu-Ching Wen – Department of Urology – Taipei Medical University

Abstract Text: Androgen deprivation therapy (ADT) is typically applied to decrease the tumor burden in advanced prostate cancer cases. However, emerging evidence of prolonged androgen receptor (AR) pathway blockage can change the archetypal course of the disease, which results in histological dedifferentiation and alterations in the lineage of prostate cancer cells. Our previous study showed that stimulation of the muscarinic acetylcholine receptor 4 (CHRM4) leads to the development of neuroendocrine differentiation (NED) in prostate cancer after ADT. Here, we aimed to investigate the role of CHRM4 in the tumor microenvironment (TME) to demonstrate its potential as a clinical predictive diagnostic for NED of prostate cancer. We identified the mechanism of how AR inhibition increases CHRM4 expression in prostate cancer after ADT. Our findings also suggest that overexpression of CHRM4 may stimulate immunosuppressive cytokine secretion from immune cells in the TME that trigger an immunosuppressive response of prostate cancer cells, leading to NED and metastasis. Immunosuppressive cytokines mediate feedback mechanisms in the TME by activating CHRM4-driven immune checkpoint pathways, promoting the progression of NED, migration, invasion, and proliferation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NED prostate cancer and evaluated the level of immunosuppressive cytokines in the TME as a prognostic biomarker for predicting NED progression in prostate cancer.