Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer

Yen Nien Liu, Wei Yu Chen, Ming Kun Liu, Hsiu Lien Yeh, Wei Hao Chen, Kuo Ching Jiang, Han Ru Li, Zi Qing Chen, Wan Hsin Wang, Wassim Abou-Kheir, Yu Ching Wen

Research output: Contribution to journalArticlepeer-review

Abstract

Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

Original languageEnglish
JournalMolecular Oncology
DOIs
Publication statusAccepted/In press - 2024

Keywords

  • androgen deprivation therapy
  • brain-derived neurotrophic factor
  • leukemia inhibitory factor
  • neuroendocrine differentiation
  • prostate cancer
  • tumor microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Genetics
  • Cancer Research

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