Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies

Hongyu Zhu; Dehuan Xie; Ying Wang; Runda Huang; Xi Chen; Yiwei Yang; Bin Wang; Yinglin Peng; Jianxin Wang; Dexin Xiao; Dai Wu; Chao-Nan Qian; Xiaowu Deng

doi:10.1016/j.ctro.2022.11.005

Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies

Clin Transl Radiat Oncol. 2022 Nov 9:38:138-146. doi: 10.1016/j.ctro.2022.11.005. eCollection 2023 Jan.

Authors

Hongyu Zhu¹, Dehuan Xie², Ying Wang¹, Runda Huang¹, Xi Chen³, Yiwei Yang⁴, Bin Wang¹, Yinglin Peng¹, Jianxin Wang⁴, Dexin Xiao⁴, Dai Wu⁴, Chao-Nan Qian⁵, Xiaowu Deng¹

Affiliations

¹ Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
² Department of Radiation Oncology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
³ Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
⁴ Institute of Applied Electronics, China Academy of Engineering Physics, NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang 621900, China.
⁵ Department of Radiation Oncology, Guangzhou Concord Cancer Center, Guangzhou 510799, China.

Abstract

Background/purpose: Investigating the antitumor effect and intratumor as well as local immune response in breast cancer-bearing mice after MV X-ray ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT).

Materials/methods: Six-week-old female C57BL/6 mice were inoculated subcutaneously with Py8119 and Py230 breast tumor cells in the inguinal mammary gland and administered 10 Gy abdominal 6 MV X-ray FLASH-RT (125 Gy/s) or CONV-RT (0.2 Gy/s) 15 days after tumor inoculation. Tumor and spleen tissues were obtained at different time points post-irradiation (PI) for analysis of immune cell infiltration using flow cytometry and immunohistochemical (IHC) staining. Intestine tissues were collected 3 days PI to evaluate normal tissue damage and immune cell infiltration.

Results: Both FLASH-RT and CONV-RT significantly delayed tumor growth. Flow cytometry showed increased CD8+/CD3 + and CD8+/CD4 + ratios, and IHC confirmed a similar increased CD8 + T cell infiltration at 2 weeks PI in Py8119 tumor tissues in both irradiation groups. No statistical difference was observed between the irradiation groups in terms of tumor growth and increased T cell infiltration in the tumor. Unexpectedly, significantly smaller spleen weight and substantially higher CD8+/CD3 + and lower CD4+/CD3 + ratios were observed in the spleens of the FLASH-RT group than in the spleens of the non-irradiated control and CONV-RT groups 4 weeks PI. Pathological analysis revealed severe red pulp expansion in several spleens from the CONV-RT group, but not in the spleens of the FLASH-RT group. Reduced intestinal damage, macrophage and neutrophil infiltration were observed in the FLASH-RT group compared with CONV-RT group.

Conclusions: FLASH-RT and CONV-RT effectively suppressed tumor growth and promoted CD8 + T cell influx into tumors. FLASH-RT can induce different splenic immune responses and reduce radiation-induced damage in the spleen and intestine, which may potentially enhance the therapeutic ratio of FLASH-RT.

Keywords: FLASH-RT; Immune response; Tumor control; Ultra-high dose rate radiotherapy.