Longitudinal Immune Responses to Radiotherapy Differentiate Progression-Free Survival Outcomes in Esophageal Cancer 2309969

Introduction We hypothesized that baseline immune composition and post-radiotherapy (RT) immune dynamics influence progression-free survival (PFS) in esophageal cancer. Methods Peripheral blood mononuclear cells collected from patients with esophageal adenocarcinoma or squamous cell carcinoma (N = 20, N = 7 progressed, median follow up: 404 days) at baseline, during and immediately post-RT, as well as ∼days 45 and 180 post-RT were analyzed by mass cytometry. Manual gating followed by cox regression, linear mixed models or unpaired t-test, with Benjamini—Hochberg correction identified associations with PFS. Results At baseline, higher proportions of total CD3+ T cells (HR = 9.66, p = 0.01) and CD4+ central memory T cells (HR = 8.55, p = 0.017) correlated with reduced PFS by cox regression. FOXP3 expression across T cell subsets was similarly linked to reduced PFS (p < 0.05). Radiotherapy induced transient lymphopenia (mean ALC decrease 0.96 K/µL) and expression of activation (HLA-DR, CD38, PD-1, CD95) and proliferation (Ki67) markers across effector, regulatory, and helper T cell subsets (all p < 0.001). Longitudinal analyses revealed that at ∼45 days post-RT, PD-1+ CD8+ T cells (HR 0.10, p = 0.042) and IFNγ CD56hi NK cells (HR 0.082, p = 0.021) were associated with improved PFS, whereas persistence of regulatory (FOXP3+) and terminally differentiated (CD57+ EMRA) phenotypes across CD4+ and CD8+ subsets was associated with progression (p < 0.05). In this initial cohort, baseline immune composition and post-RT immune remodeling distinguished patients with durable tumor control. Conclusion Patients who progressed exhibited a more regulatory immune profile at baseline that persists to ∼45 days post-RT. In contrast, immune activation across T-cell and innate populations was associated with improved PFS. Ongoing work will expand this cohort (n = 40) and compare differences in immune composition between treatment modalities.