Association of T Cell Senescence with Radiation Pneumonitis in Patients with Non-small Cell Lung Cancer

Purpose: Associations between immunosenescence and radiation pneumonitis (RP) are largely unknown. We aimed to identify a peripheral blood T cell senescence biomarker to predict RP in patients with non-small cell lung cancer (NSCLC). Methods and Materials: Patients with locally advanced NSCLC who received definitive concurrent chemoradiotherapy (dCRT) were prospectively registered (cohort 1, n=23; cohort 2, n=31). Peripheral blood was collected at baseline, during dCRT, and at 1 month post-dCRT. Patients were dichotomized to grade ≥2 (G2+) RP and grade 0-1 (G0-1) RP. Flow cytometry was performed to assess phenotypes and functional properties of T cell subsets. RP incidence was estimated via competing risk analysis. Results: Five and six patients exhibited G2+ RP following dCRT in cohorts 1 and 2, respectively. Patients with G2+ RP exhibited a more aged T cell pool and higher frequencies of senescent CD57⁺CD28⁻CD8⁺ T cells than patients with G0-1 RP at baseline, during dCRT, and at 1 month post-dCRT. These senescent cells exhibited increased granzyme B, IFN-γ, and TNF-α production. Higher baseline frequency of CD57⁺CD28⁻CD8⁺ T cells was an independent predictor of G2+ RP (hazard ratio, 8.42; 95% confidence interval, 2.58–27.45; P<0.001). Recursive partitioning analysis revealed three distinct risk groups stratified by baseline CD57⁺CD28⁻CD8⁺ T cell frequency and lung V_{20 Gy}, with 1-year cumulative G2+ RP incidences of 50.0%, 16.7%, and 0% for high-, intermediate-, and low-risk groups, respectively (P=0.002). Conclusions: Higher baseline frequencies of CD57⁺CD28⁻CD8⁺ T cells correlated with increased G2+ RP risks. Our results suggest the need for further investigation of the role of T cell senescence on radiation-induced organ damage.