Description

Radiotherapy Needs To Go Viral To Increase Responses To Checkpoint Inhibitors

Sandra Demaria, M.D.

Weill Cornell Medicine, Cornell University, New York, NY, USA

Unleashing the power of pre-existing anti-tumor T cells by blocking immune checkpoint receptors is a successful treatment for a variable portion of cancer patients across different malignancies. However, another strategy is needed for patients whose tumors escape immune-mediated control by excluding immune cells and avoiding activation of tumor-specific T cells.

Recruitment to the tumor of a Batf3-dependent subset of dendritic cells (DCs) specialized in cross-presentation of tumor-derived antigens to CD8⁺ T cells is driven by type I interferon (IFN-I) and is essential for activation of anti-tumor CD8⁺ T cells. We have recently found that radiotherapy induces cancer cell-intrinsic activation of IFN-I pathway and release of interferon-beta, mimicking a viral infection. This results in recruitment of Batf3-dependent DCs to tumors that are refractory to immune checkpoint inhibitors. Importantly, the dose and fractionation of radiation are critical for IFN-I production by irradiated cancer cells, with a lower (doses >2-4 Gy) and an upper (doses>12 Gy) threshold, creating a therapeutic window that defines the immunogenicity of radiotherapy. The molecular mechanisms that regulate this therapeutic window will be presented. Fractionation, i.e., repeated (three times) daily delivery of radiotherapy at doses within this window, amplifies the IFN-I pathway activation in the carcinoma cells, an effect that requires upregulation of IFNRA. Furthermore, the synergy of radiotherapy with anti-CTLA-4 and the induction of abscopal effects (i.e., immune-mediated rejection of non-irradiated synchronous tumors) are completely dependent on the ability of radiotherapy to induce cancer cell-intrinsic IFN-I.

These findings have critical implications for the use of radiotherapy to increase the response to immune checkpoint inhibitors in the clinic, a combination currently being tested in almost hundred ongoing trials.

Supported by NIH 1R01CA201246, Breast Cancer Research Foundation, and The Chemotherapy Foundation.