Early changes in blood-based immune gene expression as a predictor of outcomes of 177 LuPSMA radioligand therapy in metastatic castration-resistant prostate cancer.

e17066 Background: Metastatic castration-resistant prostate cancer (mCRPC) is characterized by an immunosuppressive tumor immune microenvironment (TIME), limiting the effectiveness of immune checkpoint inhibition. We developed a 38-gene blood-based immune expression panel to characterize systemic immune profiles in prostate cancer treated with ¹⁷⁷Lu-PSMA radioligand therapy (RLT). This study assessed baseline immune profiles across disease states and examined whether early post-RLT transcriptional changes are associated with clinical outcome. Methods: Blood samples were collected from age-matched controls ( n = 60), newly diagnosed PCa ( n = 22), mCRPC ( n = 29) and a subset of mCRPC patients following 1 cycle of 177 Lu-PSMA ( n = 10). Immune gene expression was measured using qPCR and TaqMan primers targeting 38 immune genes and 6 housekeeping genes, normalized by ΔCt. Differential expression was evaluated across cohorts and pre/post-RLT. Clinical outcome analyses compared responders (n = 5; OS 327–1784 days) versus non-responders (n = 5; OS 191–244 days). Statistical analyses included non-parametric testing and Chi-square. Results: Relative to controls, 19 genes were differentially expressed in PCa and 26 in mCRPC, predominantly reflecting immune suppression. Of the 19 genes, 15 were downregulated and 4 upregulated and out of the 26, 19 were downregulated and 7 upregulated. CTLA4 and PD-L1 were both significantly reduced (0.1–0.5-fold, p < 0.05) in PCa and mCRPC compared with controls. Following a single RLT cycle, CTLA4 expression normalized in mCRPC, accompanied by restoration of the associated transcription factor BATF , while PD-L1 remained unchanged. Overall, RLT reversed 79% (15/19; p < 0.05) of downregulated immune genes. Among treated patients, responders demonstrated 2–4-fold increases ( p < 0.05) in nine immune genes, including markers of T-cell infiltration, antigen presentation, cross-presentation, and macrophage activation, compared with patients experiencing early mortality. Conclusions: This blood-based 38-gene immune panel detects systemic immune dysregulation in prostate cancer and captures rapid immunomodulatory effects of ¹⁷⁷Lu-PSMA RLT. Early transcriptional changes—particularly restoration of T-cell and macrophage activation pathways—were associated with improved survival, supporting the potential utility of this assay as a non-invasive pharmacodynamic and response biomarker. These findings suggest a role for immune profiling to identify patients most likely to benefit from RLT and to inform rational combination strategies with immunotherapy.