Impact of proton versus photon (chemo)radiation on circulating immune cells in head and neck cancer

PURPOSE: Proton therapy delivers more precise radiation with less toxicity than photons. Yet, its impact on circulating immune cells in head and neck squamous cell carcinoma (HNSCC) remains poorly understood. We compared the impact of proton versus photon radiation on circulating immune cells in patients with locally advanced HNSCC undergoing definitive (chemo)radiation. PATIENTS AND METHODS: Stage III-IV HNSCC patients receiving definitive radiation (70 Gy) with or without weekly cisplatin using proton or photon therapy were enrolled. Peripheral blood was collected at baseline, during treatment, and up to one-year post-treatment. White blood cell differentiation, lymphocyte subsets, and lymphocyte function were evaluated using high-dimensional flow cytometry and functional assays. RESULTS: Twenty-seven patients were enrolled: 10 received chemoradiation (CRT) with protons, 8 radiation (RT) alone with protons, and 9 RT alone with photons. Absolute lymphocyte counts and naïve CD4+ T cells declined in all groups, while NK cells increased and memory T-cell populations remained largely unaffected, with no additional effect of concurrent cisplatin. Lymphocyte suppression persisted for up to 6 months in the CRT proton group, 3 months in the RT proton group, and 12 months in the RT photon group. Greater low-dose body irradiation (2Gy) was correlated to lower lymphocyte counts at 5 weeks and 6 months after treatment and was more common in photon-treated patients. CONCLUSIONS: Both proton and photon radiation markedly suppress circulating lymphocytes, particularly naïve CD4+ T cells, for at least three months after treatment in locally advanced HNSCC.