Radiation Dose-Volume Effects on Negative Tumor-Draining Lymph Nodes Affected T-cell Activation and Prognosis in Esophageal Cancer with Chemoradiotherapy.

Abstract

A preclinical model found that elective nodal irradiation attenuated the efficacy of radiotherapy (RT) and radio-immunotherapy. However, limited clinical studies have explored the correlation between radiation dose-volume parameters of negative tumor-draining lymph nodes (TDLN) and T-cell activation/prognosis for patients with cancer treated with definitive radiochemotherapy. Patients with locally advanced esophageal cancer undergoing definitive chemoradiotherapy (CRT) were selected from two prospective trials. Dose-volume parameters of TDLN as well as other lymphocyte-related organs at risk and lymphocyte subsets such as CD3-CD19+ B cells, CD8+CD28+ T cells, and activated T cells (CD3+CD8+HLA-DR+) before and at the end of RT were collected. Logistic analysis was utilized to correlate dose-volume parameters with reductions in lymphocyte subsets. Prognosis of TDLN irradiation was investigated through Kaplan-Meier analysis and Cox hazards models. Among 512 patients, the median mean dose of TDLN and negative non-TDLN was 25.6 and 15.1 Gy, respectively. Multivariable analyses indicated that TDLN V15 >50% was an independent predictor of poorer local recurrence-free survival (HR, 1.31; P = 0.029) and distant metastasis-free survival (HR, 1.39; P < 0.001), as well as greater reductions in CD3-CD19+ B cells (OR, 1.98; P = 0.002), CD8+CD28+ T cells (OR, 3.42; P < 0.001), and CD3+CD8+HLA-DR+ T cells (OR, 4.67; P = 0.002) after RT. A higher radiation dose-volume parameter of TDLNs in patients with esophageal cancer undergoing CRT was significantly associated with suppression of T-cell activation and a worse prognosis. Limiting the percentage of TDLN V15 may be beneficial for improving the prognosis of CRT with or without PD-1 inhibitors.