Fractionated radiotherapy combined with PD-1 pathway blockade promotes CD8 T cell-mediated tumor clearance for the treatment of advanced malignancies

Programmed death-1 (PD-1) is a T cell inhibitory receptor, expressed on recently activated and chronically stimulated CD4 and CD8 T cells (1,2). Through interacting with programmed death ligand-1 (PD-L1), PD-1 limits T cell receptor signaling, and maintains peripheral tolerance (1,2). PD-1 pathway blockade has the potential to restore effector function to exhausted T cells, thus boosting their antiviral and antitumor activity (2). This has prompted the development of PD-1/PD-L1 antibodies for treating cancer. Success in numerous preclinical studies (3-5) led to multicenter clinical trials, and FDA approval of anti- PD-1 agents (nivolumab or Opdivo^® and pembrolizumab or Keytruda^®) for the treatment of metastatic melanoma and non-small cell lung cancer (6-8). With as many as 31% of patients benefiting from treatment and median response duration lasting 2 years (8), it is not surprising that PD-1 pathway blockade, and interference with other T cell signaling checkpoints such as cytotoxic T lymphocyteassociated antigen 4 (CTLA-4), continues to generate excitement for cancer immunotherapy. Given that PD-1 and CTLA-4 blockade exert distinct effects on tumor control, combined blockade has been successful in mouse models of melanoma and clinical trials with 53% response rate (9). In order to further increase efficacy, it is necessary to understand how immunotherapy could complement already approved treatment modalities, such as chemotherapy and radiation.