Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest into the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed the CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials that evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are undergoing. In this review, we summarize the current status of knowledge regarding the changes of CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biologic mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.

Bromodomain-containing protein 4 (BRD4) is an intracellular protein that regulates expression of various cellular functions. This study investigated whether BRD4 inhibition can alter the immunomodulatory and antitumor effects of radiation therapy (RT). A murine breast cancer cell line was implanted into BALB/c mice. The dual-tumor model was used to evaluate the abscopal effects of RT. A total of 24 Gy was delivered and BRD4 inhibitor was injected intravenously. Tumor size was measured and in vivo imaging was performed to evaluate tumor growth. Flow cytometry and immunohistochemistry were performed to examine immunologic changes upon treatment. The combination of BRD4 inhibitor and RT significantly suppressed tumor growth compared to RT alone. BRD4 inhibitor reduced the size of the unirradiated tumor indicating that it may induce systemic immune responses. Expression of HIF-1α and PD-L1 in tumor was significantly downregulated by the BRD4 inhibitor. Proportion of M1 tumor-associated macrophages (TAMs) increased, and proportion of M2 TAMs decreased upon BRD4 inhibition. BRD4 inhibitor expanded CD4+ and CD8+ T cell populations and reduced the population of monocytic myeloid-derived suppressor cells (M-MDSCs). RT-induced splenic M-MDSCs decreased upon addition of BRD4 inhibitor. Therefore, addition of BRD4 inhibition significantly enhanced the systemic antitumor responses of local RT.