2402 - Investigating Thymic Dose as a Driver of Reversible T-Cell Declines after Pulsed Low Dose Rate Radiotherapy for Esophageal Cancer

Purpose/Objective(s): Radiation-induced lymphopenia (RIL) is common in esophageal cancer patients receiving chemoradiation (CRT). Pulsed low dose rate (PLDR) radiotherapy may alter radiobiologic response, but its impact on RIL is unknown. In this prospective clinical trial cohort, we characterized the magnitude and trajectory of treatment-associated T-cell depletion and recovery in esophageal cancer patients treated with PLDR CRT. Given the thymus’ role in T-cell development, we evaluated whether thymic radiation dose (TD) contributes to T-cell depletion and impaired recovery. We hypothesized that early T-cell decline may be blunted by PLDR CRT and that higher TD would correlate with greater depletion and reduced recovery.

Materials/Methods: We retrospectively analyzed 17 patients enrolled on a PLDR CRT trial for esophageal cancer. Peripheral blood was collected at predefined timepoints and analyzed by immunophenotyping. The thymus was retrospectively contoured on simulation CT per published guidelines. Thymic dosimetry (mean dose and standard DVH metrics) was extracted, and patients were dichotomized by median mean TD. Primary endpoints were: (1) change in total T cells from baseline to nadir during CRT and (2) recovery, defined as increase of total T cells from nadir to follow-up. Secondary analyses assessed temporal trends and correlations between T-cell subsets and TD. Groups were compared using the Wilcoxon signed rank test.

Results: Seventeen patients had serial immunophenotyping. TD varied widely (Table 1). From baseline to nadir, significant declines were observed in absolute lymphocyte count (ALC), CD4+ T cells, CD8+ T cells, NK cells, and other subsets in both TD strata (p<0.001). Median decreases trended greater in the lower vs higher TD group for ALC (low TD:-1478 vs high TD:-1050/µL, p=0.0576) and total T cells (low TD:-1237 vs high TD:-875/µL, p=0.0499). Similar patterns were seen for CD4+ T cells (low TD:-1080 vs high TD:-524/µL, p=0.0281), CD4+ central memory (low TD:-382 vs high TD:-234/µL, p=0.0104), and CD4+ effector memory (low TD:-278 vs high TD:-129/µL, p=0.0499). From nadir to post-RT, partial recovery occurred without significant between-group differences. Median increases were numerically but not significantly larger in the lower TD group for ALC (+800 vs +300/µL, p=0.1018), total T cells (+721 vs +241/µL, p=0.0939), and CD8+ T cells (+511 vs +64/µL, p=0.1893).

Conclusion: In this PLDR-treated cohort, marked T-cell depletion occurred without clear lymphocyte sparing. An inverse association between TD and early depletion was observed, without a clear dose–response for recovery. Larger cohorts are needed to clarify these findings.