Effects of obesity on biphasic immune remodeling of CD45⁺ circulating cells during androgen deprivation therapy in prostate cancer.

Abstract

216 Background: Androgen-deprivation therapy (ADT) is essential for advanced prostate cancer but linked to early inflammatory and cardiovascular events without clear immune mechanisms. Longitudinal immune-cell mapping during early ADT is limited. We profiled circulating CD45⁺ populations to define systemic immune shifts over 3 months of therapy. Methods: Forty-four blood samples from 19 men with treatment-naïve prostate cancer (median age 66 years; 11 Black, 8 White; 10 obese [BMI ≥ 30]) were collected at baseline (A), 1 month (B), and 3 months (C) after leuprolide. PBMC were analyzed by 45-marker CyTOF into CD4⁺/CD8⁺ T, B, NK, and plasmacytoid dendritic (pDC) cells, plus classical (cMo) and non-classical (nMo) monocytes. Mixed-effects models (participant random intercept; BMI covariate; FDR < 0.05) assessed log₂-fold-change (log₂-FC) vs baseline. Results: At baseline, CD4⁺ T cells (38 % [26–42]) dominated, followed by CD8⁺ T (22 % [17–26]), cMo (15 % [3–24]), and NK (10 % [9–15]). Non-obese men had higher cMo (20 % [16–29]) and nMo (4.8 % [2.7–7.6]), whereas obese men had greater CD4 (41 % [38–53]) and NK (12 % [10–17]) fractions (FDR ≈ 0.05 for CD4, cMo). ADT produced a biphasic pattern. At 1 month, cytotoxic clusters changed little overall (CD8 –0.06, NK –0.12 log₂-FC) but diverged by adiposity: non-obese men showed mild cytotoxic rises (CD8 +0.05, NK +0.07), whereas obese men displayed early innate gains (cMo +1.44, nMo +1.26, pDC +1.20). By 3 months, monocytes rebounded (cMo +1.08, nMo +1.48) with far greater amplitude in obese men (cMo +2.93 vs –1.14; nMo +1.89 vs +0.67). T cells contracted (CD4 –0.66, CD8 –0.37). No subset met FDR < 0.05 after correction. Conclusions: ADT drives a biphasic remodeling of circulating CD45⁺ immunity—an early, adiposity-modulated cytotoxic shift followed by an obesity-amplified monocyte rebound. These data highlight how metabolic state shapes immune plasticity under androgen deprivation and may inform cardio-oncologic risk. Baseline characteristics of men initiating ADT. Characteristic Total (n = 19) Non-obese (n = 9) Obese (n = 10) Age, years (median [IQR]) 66 (61–71) 65 (60–70) 67 (63–72) Race, n (%) Black / White 11 (58) / 8 (42) 5 (56) / 4 (44) 6 (60) / 4 (40) BMI, kg m⁻² (mean ± SD) 31.2 ± 4.6 27.0 ± 2.1 34.9 ± 3.1 Baseline CD45⁺ composition (median % [IQR]) – CD4 T cells 38 (26–42) 31 (21–34) 41 (38–53) – CD8 T cells 22 (17–26) 22 (16–23) 20 (18–27) – Classical monocytes (cMo) 15 (3–24) 20 (16–29) 3 (1–13) – Non-classical monocytes (nMo) 2 (2–6) 5 (3–8) 2 (1–2) – NK cells 10 (9–15) 9 (8–11) 12 (10–17) – Plasmacytoid DC (pDC) 0.24 (0.11–0.51) 0.34 (0.24–0.56) 0.13 (0.08–0.35) – B cells 3.8 (2.8–4.6) 4.4 (3.0–5.3) 3.4 (2.1–3.8) Abbreviations: BMI, body-mass index; IQR, interquartile range; PBMC, peripheral-blood mononuclear cells; DC, dendritic cells; cMo, classical monocytes; nMo, non-classical monocytes.