Stereotactic Radiation Therapy Augments Antigen-Specific PD-1–Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen

Abstract

The immune-modulating effects of radiation therapy have gained considerable interest recently 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 the development of antigen-specific T and B cell-mediated immune responses. These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 therapy 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.

Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade

“…In most of these preclinical studies enhanced tumor immune responses have been generated by high-doses of hypofractionated RT in combination with a range of immunomodulatory agents (19,(21)(22)(23)(24)(25). In contrast, the Research. on June 1, 2017.…”

Checkpoint inhibitors and radiation treatment in Hodgkin’s lymphoma

“…The changes in the immune profiles of patients treated with radiation and immunotherapy with-the so-called abscopal effect-was described recently and underlined with impressive clinical data in melanoma treatment [10,11]. As mentioned before these results are well known from preclinical data [12][13][14] and there is still little knowledge why the effects are seen frequently in mice models and rarely in oncologic patients.…”

Irradiation and immunotherapy: From concept to the clinic

“…Additional data suggest that RT in combination with anti-PD-1 therapy induces an antigen-specific immune response in models of melanoma and breast cancer. 34 The interaction of the immunosuppressive cytokine transforming growth factor b (TGF-b) with the PD-1/PD-L1 axis appears to be a critical signal mediating the antitumor effects of RT. The combination of TGF-b blockade with RT resulted in tumor rejection in a poorly immunogenic breast cancer model, but up-regulation of PD-L1/L2 limited the durability of control.…”