Impact of Proton versus Photon (Chemo)radiation on Circulating Immune Cells in Head and Neck Cancer

Proton therapy delivers more precise radiation (RT) with less toxicity than photons. However, 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 RT on circulating immune cells in patients with locally advanced HNSCC undergoing definitive (chemo)radiation [(C)RT].

Patients with stage III to IV HNSCC receiving definitive RT (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 1 year after treatment. White blood cell differentiation, lymphocyte subsets, and lymphocyte function were evaluated using high-dimensional flow cytometry and functional assays.

Twenty-seven patients were enrolled: Ten received CRT with protons, eight received RT alone with protons, and nine received RT alone with photons. Absolute lymphocyte counts and naïve CD4+ T cells declined in all groups, whereas 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 (2 Gy) was correlated with lower lymphocyte counts at 5 weeks and 6 months after treatment and was more common in photon-treated patients.

Both proton and photon RT markedly suppress circulating lymphocytes, particularly naïve CD4+ T cells, for at least 3 months after treatment in locally advanced HNSCC.

Proton RT is increasingly utilized for head and neck cancer. However, its impact on systemic immunity remains unclear. We demonstrated that both proton and photon RT caused prolonged suppression of circulating lymphocytes for at least 3 months. Naïve CD4+ T cells were preferentially depleted, whereas memory T-cell populations were largely spared. These findings highlight the importance of considering immune effects and minimizing off-target lymphocyte exposure when combining radiotherapy with immunotherapy.