Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Prostate cancer (PCa) progression involves complex interactions within the tumor microenvironment (TME).
• Prostate stromal cells influence PCa aggressiveness and immune evasion, but the mechanisms are not fully understood.
• Androgen deprivation therapy (ADT) can paradoxically promote an immunosuppressive TME.

Purpose of the Study:

• To investigate the role of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in ADT-induced immunosuppression and neuroendocrine differentiation (NED) in PCa.
• To elucidate the crosstalk between PCa cells and prostate stromal cells mediated by LIF/LIFR signaling.
• To explore the therapeutic potential of targeting the LIF/LIFR pathway.

Main Methods:

• Analysis of LIF/LIFR pathway activation in PCa and stromal cells following ADT.
• Investigating the effects of LIF/LIFR signaling on PCa cell differentiation and immune checkpoint expression.
• Utilizing LIFR knockdown in stromal cells to assess its impact on PCa.
• Measuring brain-derived neurotrophic factor (BDNF) levels in relation to LIF/LIFR signaling and clinical outcomes.
• Correlating BDNF, PDL1, and immunosuppressive signatures in metastatic castration-resistant PCa (CRPC) patient samples.

Main Results:

• ADT activates LIF/LIFR signaling in both PCa and stromal cells, creating an immunosuppressive TME.
• LIF/LIFR activation in PCa cells drives NED and upregulates immune checkpoint expression (e.g., PDL1).
• LIFR expression in prostate stromal cells contributes to PCa NED and immunosuppression.
• ADT-induced LIF/LIFR signaling upregulates BDNF, promoting PCa aggressiveness and immune evasion.
• Elevated BDNF levels correlate with PDL1 and immunosuppressive signatures in metastatic CRPC.

Conclusions:

• The LIF/LIFR pathway is a critical link between ADT, NED, and immunosuppression in prostate cancer.
• Targeting LIF/LIFR signaling and its downstream effector BDNF may represent a novel therapeutic strategy for CRPC.
• Stromal cell-mediated LIF/LIFR signaling plays a significant role in modulating the PCa TME and treatment response.