Radiation-Induced Fibrotic Tumor Microenvironment Regulates Anti-Tumor Immune Response.

High linear energy transfer (LET) radiation, such as neutron radiation, is considered more effective for the treatment of cancer than low LET radiation, such as X-rays. We previously reported that X-ray irradiation induced endothelial-to-mesenchymal transition (EndMT) and profibrotic changes, which contributed to the radioresistance of tumors. However, this effect was attenuated in tumors of endothelial-specific Trp53-knockout mice. Herein, we report that compared to X-ray irradiation, neutron radiation therapy reduced collagen deposition and suppressed EndMT in tumors. In addition to the fewer fibrotic changes, more cluster of differentiation (CD8)-positive cytotoxic T cells were observed in neutron-irradiated regrowing tumors than in X-ray-irradiated tumors. Furthermore, lower programmed death-ligand 1 (PD-L1) expression was noted in the former. Endothelial-specific Trp53 deletion suppressed fibrotic changes within the tumor environment following both X-ray and neutron radiation therapy. In particular, the upregulation in PD-L1 expression after X-ray radiation therapy was significantly dampened. Our findings suggest that compared to low LET radiation therapy, high LET radiation therapy can efficiently suppress profibrotic changes and enhance the anti-tumor immune response, resulting in delayed tumor regrowth.

The efficacy of neutron radiation therapy in treating salivary gland malignancies.

OBJECTIVES: Radiation therapy is commonly used to treat head and neck malignancies. While there is abundant research regarding photon radiation therapy, literature on neutron radiotherapy (NRT) and oral complications is limited. This study aims to determine: (1) the 6-year and 10-year locoregional control and survival rates, (2) factors associated with locoregional control and survival and (3) the frequency of oral complications in patients undergoing NRT for salivary gland malignancies. MATERIALS AND METHODS: This is a retrospective cohort study. The sample was composed of patients with salivary gland malignancies treated with NRT between 1997 and 2010. Data were extracted from patient charts, telephone surveys, and social security records. Multivariate competing risk and Cox regression models were used to assess predictors of locoregional control and survival. RESULTS: The sample was composed of 545 subjects with a mean age of 54.2 years (±16). The predominant tumor and location were adenoid cystic carcinoma (47%) and the parotid (56%). Multivariate analysis indicated that positive surgical margins, biopsied/inoperable malignancies, neck involvement, and lymphovascular invasion were prognostic risk factors associated with decreased survival. The 6- and 10-year locoregional control rates were 84% and 79%. The 6- and 10-year survival rates were 72% and 62%. Osteoradionecrosis developed in 3.4% of subjects. CONCLUSIONS: The 6- and 10-year locoregional control and survival rates compare favorably to rates reported for conventional photon radiation. Osteoradionecrosis rates were comparable to that of photon radiation treatment (2-7%). Given the potential benefits of NRT, healthcare professionals should be educated regarding its indications and oral complications.

Neutron Radiation Therapy for Treatment of Refractory Merkel Cell Carcinoma.

We describe the first reported use of neutron radiation therapy for successful palliation of treatment refractory Merkel cell carcinoma. The patient was a 78-year-old man with Merkel cell carcinoma involving the scalp and bilateral cervical lymph nodes. The extensive coalescing scalp lesions were locally destructive, painful, and highly detrimental to his overall quality of life, and he had previously progressed through 3 courses of conventional x-ray-based radiation therapy and multiple immunotherapy regimens. We treated him with neutron radiation therapy, and he experienced a complete and durable local response with minimal toxicity. High linear energy transfer particle therapy approaches deserve consideration as a treatment option in cancers that are refractory to standard radiation therapy.