Immunosuppressive role of BDNF in therapy‐induced neuroendocrine prostate cancer

• Published in: Molecular oncology Vol. 18; no. 6; pp. 1665 - 1686
• Main Authors: Liu, Yen‐Nien, Chen, Wei‐Yu, Liu, Ming‐Kun, Yeh, Hsiu‐Lien, Chen, Wei‐Hao, Jiang, Kuo‐Ching, Li, Han‐Ru, Chen, Zi‐Qing, Wang, Wan‐Hsin, Abou‐Kheir, Wassim, Wen, Yu‐Ching
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2024; John Wiley and Sons Inc; Wiley
• Subjects: Androgen Antagonists - pharmacology; Androgen Antagonists - therapeutic use; androgen deprivation therapy; Androgens; Animals; Apoptosis; Biomarkers; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Castration; Cell death; Cell Differentiation; Cell growth; Cell Line, Tumor; Humans; Immune checkpoint; Immune evasion; Immunosuppression; Kinases; Leukemia; Leukemia inhibitory factor; Leukemia Inhibitory Factor - metabolism; Leukemia Inhibitory Factor Receptor alpha Subunit - genetics; Leukemia Inhibitory Factor Receptor alpha Subunit - metabolism; Ligands; Male; Metastases; neuroendocrine differentiation; Neuroendocrine Tumors - immunology; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Penicillin; Polymerase chain reaction; Prostate Cancer; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Signal Transduction - drug effects; Stromal cells; Stromal Cells - metabolism; Stromal Cells - pathology; Tumor Microenvironment; Tumor Microenvironment - immunology; Tumors; Variance analysis; Basel Switzerland; United States > US; Switzerland; androgen deprivation therapy; prostate cancer; tumor microenvironment; leukemia inhibitory factor; brain‐derived neurotrophic factor; neuroendocrine differentiation
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13614

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. Activation of LIF/LIFR/STAT3 signaling in the prostate cancer tumor microenvironment triggers BDNF production, linked to heightened PDL1 expression and neuroendocrine differentiation in prostate cancer cells. This pathway is crucial in stromal cells for regulating immune suppression and checkpoint responses, suggesting potential prognostic markers and therapies to combat immune evasion and neuroendocrine differentiation in prostate cancer.