Immune determinants of leuprolide-associated cardiovascular risk in prostate cancer

Background and hypothesis Leuprolide, the most widely used gonadotropin-releasing hormone receptor (GnRHR) agonist for androgen deprivation therapy (ADT) in prostate cancer (PC), is associated with increased risk of cardiovascular events (CVE), but the underlying mechanisms remain poorly defined. Given the pivotal contribution of circulatory immune components to cardiovascular complications, we hypothesized that leuprolide alters the cardiac immune microenvironment and that pre-existing circulating immune phenotypes determine the patient vulnerability to CVE. Methods We integrated spatial transcriptomics of coronary plaque and cardiac tissues from leuprolide-treated mice, with longitudinal immune profiling blood leukocytes of PC patients receiving leuprolide. Spatial analyses examined treatment-associated changes in cellular composition, inferred receptor signaling, transcriptional programs and intercellular communication across coronary plaque and non-plaque cardiac compartments. Peripheral blood from 25 patients was profiled longitudinally by multiparametric flow cytometry together with measurement of circulating adipocytokines. Results Leuprolide selectively reorganized the coronary plaque microenvironment in mice, characterized by altered GnRHR- and androgen receptor-signaling in plaque fibroblasts, organization of T+B lymphoid aggregates, and enrichment of inflammatory M1-like macrophages exhibiting interferon and mesenchymal-remodeling programs. These changes accompanied by non-plaque alteration, particularly ventricular cardiomyocyte hypertrophy in murine heart. Approximately ∼44% of PC patients receiving leuprolide had CD8 + T cell phenotype that associated with treatment-related CVE, including ventricular dysfunctions. A composite signature incorporating Tc1 (type 1 cytotoxic T cells), CD8 + effector-memory, CD8 + transitional-memory and CD8 lo T cell populations distinguished this susceptible phenotype. Conclusions These findings establish cardiovascular immune remodeling as a framework for leuprolide-associated CVE and nominate pre-existing circulating CD8 + T cell states as candidate biomarkers for prospective ADT-risk stratification. Novelty and Significance The mechanisms underlying cardiovascular complications of GnRH receptor agonist therapy remain incompletely understood. We combined spatial transcriptomic analysis of coronary plaque and cardiac tissue with longitudinal immune profiling of patients with prostate cancer receiving leuprolide. Leuprolide was associated with a plaque-specific immune responses, involving altered fibroblast GnRH-signaling, increased T+B lymphoid aggregates, and inflammatory M1-like macrophages with interferon and mesenchymal-remodeling programs. In contrast, histologically normal vasculature showed a predominantly M2-like macrophage response. Changes outside the plaque included adipose-stromal remodeling and an increase in hypertrophic ventricular cardiomyocytes. In patients, a pre-existing CD8 + T cells had phenotype associated with treatment-related cardiovascular events, including ventricular dysfunction. A signature comprising Tc1, CD8 + effector-memory, CD8 + transitional-memory, and CD8 lo T cell populations distinguished this immune phenotype. These observations suggest that the cardiovascular response to leuprolide is influenced by both the local tissue environment and the pre-existing systemic immune state. The circulating T-cell signature warrants prospective validation as a potential approach to identify patients who may be more susceptible to cardiovascular complications during androgen deprivation therapy.