GPNMB⁺ MDSCs Mediate Radiation-Induced Immune Suppression in Prostate Cancer and Are Targetable to Improve Systemic Control.

Abstract

Stereotactic body radiation therapy (SBRT) provides excellent local control for localized prostate cancer (PC); however, systemic relapse remains the primary cause of mortality in high-risk patients, underscoring the need to understand and therapeutically address radiation-induced immune suppression. Here, we identify a previously unrecognized myeloid checkpoint pathway driven by GPNMB⁺ myeloid-derived suppressor cells (MDSCs) as a dominant systemic response to clinical SBRT and demonstrate a tractable strategy to counter it. We used paired peripheral blood samples from patients treated with SBRT to measure systemic MDSCs by flow cytometry, followed by ex vivo functional assays with patient PBMCs. For further characterization, we used a syngeneic PC RM-9 tumor model. RT-PCR and luciferase assays determined the mechanism observed. We observed a selective and reproducible expansion of GPNMB⁺ MDSCs accompanied by enhanced T-cell suppression. GPNMB blockade in patient's PBMCs rapidly and consistently restored T-cell activity, directly supporting the clinical feasibility of targeting this pathway. Likewise, in tumor-bearing mice, radiation upregulated GPNMB on MDSCs and its ligand SDC4 on tumor-infiltrating T cells. Therapeutically, combining anti-GPNMB antibody with radiation significantly improved local tumor control and reduced metastatic burden compared with radiation alone and outperformed PD-L1 blockade. Transcriptomic and mechanistic analyses identified MITF as a key regulator of radiation-induced GPNMB expression. Together, these findings define an actionable RT → MDSC → GPNMB myeloid checkpoint that suppresses T-cell immunity in prostate cancer and demonstrate that targeting this pathway reverses radiation-induced immune suppression across human and murine systems. This work establishes a strong translational rationale for integrating MDSC-targeted therapy with SBRT to improve systemic control in localized high-risk prostate cancer.