An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models

• Published in: International journal of radiation oncology, biology, physics Vol. 103; no. 3; pp. 697 - 708
• Main Authors: Markovsky, Ela, Budhu, Sadna, Samstein, Robert M., Li, Hongyan, Russell, James, Zhang, Zhigang, Drill, Esther, Bodden, Chloe, Chen, Qing, Powell, Simon N., Merghoub, Taha, Wolchok, Jedd D., Humm, John, Deasy, Joseph O., Haimovitz-Friedman, Adriana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Carcinoma, Lewis Lung; CD8-Positive T-Lymphocytes - cytology; Cell Line, Tumor; Disease Models, Animal; DNA Damage; Immune System - radiation effects; Intercellular Adhesion Molecule-1 - chemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Microscopy, Fluorescence; Neoplasm Transplantation; Neoplasms - radiotherapy; Radiotherapy - methods; Radiotherapy Dosage; T-Lymphocytes - radiation effects
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2018.10.009

This study examined tumor growth delay resulting from partial irradiation in preclinical mouse models. We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2 × 2 cm collimator on a microirradiator. Radiation response was modulated by treatment with anti-CD8 and anti—intercellular adhesion molecule (anti-ICAM) antibodies. Similar experiments were performed using the less immunogenic Lewis lung carcinoma mouse model. Tumor growth delay and γ-H2AX phosphorylation were measured, and immune response was assessed by immunofluorescence and flow cytometry at 1 and 7 days after radiation therapy. Tumor expression of cellular adhesion molecules was also measured at different times after radiation therapy. Partial irradiation led to tumor responses similar to those of fully exposed tumors in immunocompetent mice, but not in nude mice. After a single dose of 10 Gy, infiltration of CD8+ T cells was observed along with increased expression of ICAM. The response to 10 Gy in hemi-irradiated tumors was abrogated by treatment with either anti-CD8 or anti-ICAM antibodies. Similar responses were obtained in the less immunogenic Lewis lung carcinoma mouse model delivering 15 Gy to half the tumor volume. Treatment with FTY720, a compound that inhibits T-cell egress from lymph nodes, did not affect tumor response at the time of CD8+ T cells infiltration in the nonirradiated area of the tumor. This result indicated that the most likely source of these cells is the irradiated portion of the hemi-irradiated tumors. In addition, a significant abscopal effect was observed after partial irradiation with a single dose of 10 Gy in the 67NR model. In these models, radiation controls tumor growth both directly through cell killing and indirectly through immune activation. This outcome raises the possibility that this effect could be induced in the clinic.