Work

Proton and Photon Radiation Differentially Reshape Memory T Cell Responses in Esophageal Carcinoma

Year: 2026

Type: article

Abstract: Background and Aims: To further investigate the superior biological effectiveness of carbon ions and the stealth-bomber paradigm, we compared the therapeutic and immunomodulatory effects of carbon ion, proton, and photon radiotherapy delivered at biologically equivalent doses in preclinical HNSCC models, alone or combined with anti-PD-1 immunotherapy.We investigated these effects in an immunocompetent murine model and integrated a complementary embryonated chicken egg chorioallantoic membrane (CAM) xenograft model.Methods: SCCVII tumors were established in C3H mice and treated with photons, protons, or carbon ions (5 × 2 GyE), with or without anti-PD-1.Tumor growth, survival, and vaccine-like protection were assessed in mouse, together with immune-related transcriptomic profiling and immunohistochemical (IHC) analyses of tumors.In parallel, human FaDu cancer cells were grafted onto the CAM of embryonated chicken eggs and tumors were irradiated at biologically equivalent single doses: 5 Gy carbon ions and 10 Gy photons or protons.Tumor volume and weight, as well as IHC markers, were quantified.Results: At biologically equivalent doses in mice, carbon ions achieved superior tumor control compared with photons and protons.Combination with anti-PD-1 improved therapeutic efficacy across all radiotherapy modalities, but carbon ions plus anti-PD-1 was associated with the highest survival and the strongest vaccinelike protection.Carbon ions most effectively reduced immunosuppressive marker expression while enhancing immunogenic cell death and M1 macrophage polarization.In the CAM model, a clear efficacy gradient was observed, with carbon ions inducing the greatest reductions in tumor volume and weight, while protons showed intermediate activity between carbon ions and photons, consistent with the hierarchy observed in the murine model.Conclusions: Radiation quality markedly influences antitumor efficacy and immune remodeling, even at biologically equivalent doses.Carbon-ion radiotherapy shows the strongest therapeutic benefit and favorable synergy with anti-PD-1, supporting its relevance for future immuno-radiotherapy strategies in poorly immunogenic tumors such as HNSCC.Furthermore, the CAM model provides a practical, ethics-light system for ion-and beam-quality intercomparisons (e.g.helium, oxygen, FLASH irradiation) and rapid regimen/combination screening.Supported by Ligue contre le Cancer -Comité Haute-Savoie, LabEX PRIMES (ANR-11-LABX-0063), EU H2020 HITRIplus project (GA 101008548)

Source: International Journal of Particle Therapy

DOI: 10.1016/j.ijpt.2026.101798