Local radiotherapy modulates the tumor immune microenvironment: The role of type I interferons

Nearly seventy percent of cancer patients receive radiotherapy (RT) during the course of treatment making it one of the most widely employed anti-cancer therapies. The efficacy of RT is believed to reside in the capacity of radiation to mediate lethal DNA damage to tumor cells leading to tumor regression. In addition to the direct effects of radiation in mediating DNA damage, radiation can augment the capacity of tumor cells to interact with, and be recognized by, the host immune system. In particular, we demonstrate that endogenous CD8+ T cells play an essential role in the efficacy of local RT across several murine tumor cell types with a wide range of intrinsic radiosensitivities. Treatment of established tumors with local radiation increased tumor infiltration by T cells that was associated with increased expression of local T cell attractive chemokines. In addition, T cell infiltration was biased towards CD8 + T cells which altered the proportions of T cell subsets in the local microenvironment to generate a favorable effector:suppressor T cell ratio. Importantly, local RT did not increased the systemic pool of tumor antigen-specific CD8+ T cells and was unable to mediate a significant abscopal effect against a distant untreated tumor in a model of disseminated disease. Combination local RT and systemic immunotherapy could further enhance the local effect. In an effort to understand the mechanisms of tumor control following treatment with local RT, we identified type I interferon (IFN) as an essential component in the host immune response. The efficacy of local RT was dramatically diminished when host responsiveness to type I IFN was abolished, and bone marrow derived hematopoietic cells are demonstrated to be the essential targets of host type I IFN. The local accumulation of myeloid derived suppressor cells (MDSCs) was dramatically increased in tumors arising in type I IFN nonresponsive hosts and was further augmented by local radiation leading to exaggerated local immune suppression. Therapeutic depletion of MDSCs in type I IFN nonresponsive hosts was sufficient to restore CD8 + T cell mediated tumor regression following treatment with local RT. Collectively, our results suggest that the major function of local radiation with regard to host immunity is to increase effector T cell infiltration into the local tumor microenvironment generating a favorable environment for immune-mediated tumor control. In addition, host type I interferon is essential for limiting the local accumulation of immune suppressive myeloid cells therefore fostering a tumor microenvironment suitable for T cell mediated tumor regression. This work begins to unravel the complex interplay between conventional cancer therapy and host immunity that will likely provide a groundwork for the rational combination of radiotherapy and immunotherapy.