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A large body of preclinical data supports the ability of radiation to modulate cancer cell intrinsic immunogenicity as well as the tumor immune microenvironment and increase responses to immune checkpoint inhibitors (ICI). Early reports of recovered responses to ICI in patients receiving radiation therapy (RT) have raised a lot of enthusiasm for the potential of radiation to benefit patients beyond its traditional role in local cancer control or palliation. Prospective clinical trials testing combinations of RT with ICI have provided proof-of-principle evidence that radiation can induce tumor-specific T cell responses in patients treated with ICI. However, evidence that adding RT to ICI provides a reproducible benefit has been for the most part elusive in randomized trials. This gap in translation highlights gaps in knowledge about the factors that affect the anti-tumor immune response to RT+ICI combinations. It is becoming clear that the role of radiation-specific factors (such as dose, fractionation and field), as well as tumor- and host-specific factors need to be better understood in order to harness radiation’s new role as an adjuvant to cancer immunotherapy.

I will briefly summarize our experience in characterizing the mechanisms that are central to RT ability to increase responses to ICI in mice and patients, and present new insights about the signals from irradiated cancer cells that activate interferon type I in antigen-presenting cells, a key requirement for in situ vaccination by radiation. Our recent single cell analysis in preclinical models highlights the fact that there are qualitative and quantitative changes in the intratumoral T cell compartment in tumors treated with RT plus anti-CTLA4 that cannot be predicted by analyzing the effects of each individual treatment. Finally, our preclinical data show that RT is necessary but often not sufficient to induce responses to ICI in the majority of tumor-bearing hosts, and additional treatments targeting pre-existing or RT-induced barriers are required.

Overall, these data can help the design of clinical studies that test precision combinations of RT and immunotherapy and provide better and more reliable clinical benefits to patients.