(H-307) RAPID RECRUITMENT OF MONOCYTES DICTATES THE EFFICACY OF IMAGE-GUIDED RADIOTHERAPY

Image-guided conformal radiotherapy (CRT), commonly used as a standard of care for cancer patients, is designed to minimize radiation toxicity to healthy tissues. However, most of our knowledge of immune responses established during radiotherapy comes from non-conformal pre-clinical radiation approaches that do not resemble clinical practice. Consequently, we lack an understanding of the immune response induced by CRT. Here, we adopted a pre-clinical image-guided CRT to treat tumor-bearing mice. We compared the immune response promoted by CRT with that of a preclinical non-conformal approach that shields the small animal from radiation using a shield, i.e., shield radiotherapy (SRT). We found that CRT is superior at tumor elimination in comparison to SRT. The survival benefit of CRT is mediated by an early recruitment of monocytes that minimally differentiate into tumor-associated macrophages (TAM) or dendritic cells (DC), but instead upregulate major histocompatibility complex II (MHCII) and costimulatory molecules. These monocytes produce high levels of type I interferon (IFN-I) in the tumor microenvironment, resulting in the activation of effector polyfunctional CD8+ tumor-infiltrating lymphocytes (TILs) that reduce tumor burden. This innate immune mechanism is absent in SRT. Indeed, SRT-recruited monocytes differentiate into TAM, resulting in minimal CD8+ T cell activation and tumor progression. We establish that the discrepancy between these two modes of RT is mediated by healthy tissue radiation damage. Our work unravels an immunostimulatory function of monocytes during clinically relevant image-guided modes of RT and demonstrate that limiting healthy tissue radiation damage has a positive impact on the overall anti-tumor immune response.