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Abstract
Local radiotherapy (RT) is important to manage metastatic triple-negative breast cancer (TNBC). Although RT primarily reduces cancer cells locally, this control can be enhanced by triggering the immune system via immunotherapy. RT and immunotherapy may lead to an improved systemic effect, known as the abscopal effect. Here, we analyzed the antitumor effect of combination therapy using RT with an anti-programmed cell death-1 (PD-1) antibody in primary tumors, using poorly immunogenic metastatic mouse mammary carcinoma 4T1 model. Mice were injected subcutaneously into both flanks with 4T1 cells, and treatment was initiated 12 days later. Mice were randomly assigned to three treatment groups: (1) control (no treatment with RT or immune checkpoint inhibitor (ICI)), (2) RT alone, and (3) RT+ICI. The same RT dose was prescribed in both RT-alone and RT+ICI groups as 10Gy/fx in two fractions and delivered to only one of the two tumor burdens injected at both sides of flanks. In the RT+ICI group, 200 µg fixed dose of PD-1 antibody was intraperitoneally administered concurrently with RT. The RT and ICI combination markedly reduced tumor cell growth not only in the irradiated site but also in non-irradiated sites, a typical characteristic of the abscopal effect. This was observed only in radiation-sensitive cancer cells. Lung metastasis development was lower in RT-irradiated groups (RT-only and RT+ICI groups) than in the non-irradiated group, regardless of the radiation sensitivity of tumor cells. However, there was no additive effect of ICI on RT to control lung metastasis, as was already known regarding the abscopal effect. The combination of local RT with anti-PD-1 blockade could be a promising treatment strategy against metastatic TNBC. Further research is required to integrate our results into a clinical setting.

Affiliations

Haa-Na Song  1   2   3 , Hana Jin  2   4 , Jung-Hoon Kim  1   2   3 , In-Bong Ha  2   3   5 , Ki-Mun Kang  2   3   6 , Hoon-Sik Choi  2   3   6 , Ho-Jin Jeong  2   3   5 , Min-Young Kim  7 , Hye-Jung Kim  2   4 , Bae-Kwon Jeong  2   3   5
1 Division of Hemato-Oncology, Department of Internal Medicine, Gyeongsang National University of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea.
2 Institute of Health Science, Gyeongsang National University, Jinju 52727, Korea.
3 Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Korea.
4 Department of Pharmacology, School of Medicine, Gyeongsang National University, Jinju 52727, Korea.
5 Department of Radiation Oncology, Gyeongsang National University of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea.
6 Department of Radiation Oncology, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon 51472, Korea.
7 Division of Endocrinology, Department of Internal Medicine, Gyeongsang National University of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea.