Targeting regulatory T cells in the prostate cancer microenvironment: From mechanisms to therapeutics (Review)

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Prostate cancer (PCa) is a complex disease where tumor microenvironment, particularly regulatory T cells (Tregs), significantly impacts immune evasion and progression.
• Understanding Treg development, function, and regulatory networks within the PCa tumor microenvironment is crucial for effective treatment strategies.

Purpose of the Study:

• To systematically review the role of Tregs in prostate cancer, focusing on their heterogeneity, spatial distribution, and impact on immune evasion.
• To critically evaluate current and emerging therapeutic strategies targeting Tregs in PCa, including immunotherapies and combination approaches.
• To discuss challenges and prospects for translating Treg-targeting therapies into clinical practice.

Main Methods:

• Systematic review of existing literature, including synthesis of spatial transcriptomic and single-cell RNA-sequencing data.
• Critical evaluation of preclinical and clinical data on immunotherapies targeting Tregs.
• Analysis of Treg-directed approaches combined with standard therapies like androgen deprivation therapy (ADT) and radiotherapy.

Main Results:

• Treg functional heterogeneity and spatial distribution within the tumor stroma are critical determinants of immune evasion in PCa.
• High stromal Treg density correlates with an increased risk of biochemical recurrence, and specific activated Treg subsets are prevalent in high-Gleason score tumors.
• While anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monotherapy showed limited efficacy, novel antibody designs demonstrate significant Treg depletion in preclinical models; combination therapies show promise.

Conclusions:

• Targeting specific Treg subsets (e.g., CCR4+, GARP+) and integrating these approaches with ADT or radiotherapy may mitigate treatment-induced Treg expansion and improve outcomes.
• Patient stratification using Treg-related biomarkers is essential for the successful clinical translation of Treg-targeting therapies in prostate cancer.
• Further research is needed to overcome challenges and optimize Treg-directed strategies for PCa treatment.