Intralesional Bacillus Calmette–Guérin injections and hypo-fractionated radiation synergistically induce systemic antitumor immune responses

Abstract

Radiotherapy, an important treatment for multiple malignancies, produces systemic anti-tumor effects in combination with immunotherapies, especially immune checkpoint inhibitors (ICBs). However, for some patients who do not respond to ICB treatment or show ICB-induced autoimmune symptoms, new alternatives need to be explored. Innovative immunomodulatory strategies, including the administration of immunostimulants, could be used to improve the immunogenicity induced by radiotherapy. In this study, we explored the synergistic effect of Bacillus Calmette-Guérin (BCG) combined with hypo-fractionated radiotherapy (H-RT) in inducing anti-tumor immune responses. We observed the systemic and abscopal effects of this combination in mice with 4T1 breast cancer. H-RT combined with BCG could remodel the immune microenvironment and alleviate leukocyte-like responses by increasing the infiltration of CD8+T cells, promoting the maturation of dendritic cells (DCs), decreasing the infiltration of immunosuppressive cells, and downregulating the expression of immunosuppressive cytokines. Therefore, this combination could enhance the systemic anti-tumor response, leading to the regression of untreated synchronous tumors and a decrease in the systemic metastatic burden. These results highlight the potential of BCG in assisting antitumor therapy and the therapeutic potential of this combination treatment.