The immune-modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. However, additional pre-clinical studies are needed to demonstrate the antigen-specific nature of radiation induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image guided stereotactic radiotherapy delivered to B16-OVA Melanoma or 4T1-HA Breast Carcinoma tumors resulted in development of antigen-specific T-cell and B-cell mediated immune responses. These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that radiotherapy increased the percentage of antigen-experienced T-cells and effector memory T-cells. Mechanistically we found that radiotherapy up-regulates tumor associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors. These findings demonstrate the ability of radiotherapy to prime an endogenous antigen-specific immune response and provide additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic.
- Received October 16, 2014.
- Revision received December 2, 2014.
- Accepted December 3, 2014.
- Copyright © 2014, American Association for Cancer Research.