Project Summary In addition to direct killing of rapidly proliferating tumor cells, radiation therapy (RT) modifies tumor immunity. RT increases the expression and release of tumor-associated antigens, induces immunogenic cell death, and releases danger signals and chemokines that recruit immune cells to the tumor microenvironment (TME). RT can also enhance tumor killing by increasing the number of tumor-infiltrating immunostimulatory cells and inducing the expression of neoantigens. However, RT also stimulates the recruitment of other myeloid derived immune cell subsets that can have tumor permissive phenotypes. The overall balance between these immune stimulatory and suppressive effects of radiation ultimately predicts whether local tumor treatment with RT generates an effective and durable systemic anti-tumor immune response. We hypothesize that RT (and in particular SOC CRT) limits the development of long-term anti-tumor immunity in resistant tumors by disproportionately increasing the number and tumor permissive phenotypes of myeloid derived cells (MDCs) in the TME. The Washington University MicroEnvironment Tumor Effects Of Radiotherapy (METEOR) Center will enable testing of this hypothesis via a dynamic Molecular Characterization Trial with closely integrated Research Projects, Shared Resource Cores, and Cross Training Core. We will leverage our institutional expertise in genomics, proteomics, tumor metabolism and immunology to take a “deep dive” into CRT induced tumor and TME co-evolution. Our overall vision is that immunosuppressive SOC CRT associated changes in the immune TME can be further targeted to improve systemic anti-tumor immune responses after RT. Although our preliminary data implicates two immune TME cell types, macrophages and dendritic cells, our research design is intended to allow for detailed study of CRT related effects on multiple cell types within the TME. As such, our Center can adapt and incorporate new findings in other cell types during the course of funding of this grant through pilot projects and data sharing. Importantly, tumor cells and the TME are influenced by the tissue of origin of the tumor. Thus, it is important to use this approach to study multiple tumor types to establish what are the common (and tumor specific) mechanisms of CRT related immunosuppression. METEOR will thus serve as a hub to share this approach with other ROBIN Centers studying different tumor types. Since the analytic approach through our Shared Resource Cores requires only small biopsies, this will allow other Centers to send limited specimens to us for analysis. Furthermore, through our Administrative and Cross Training Cores, we will host faculty and trainees from other ROBIN centers and share with them our resources, educational materials and approach which will bring added value to the ROBIN network. As a result of this work we will be well positioned to apply for a future NIH T32 focused on training, disseminating and advancing multidisciplinary informatic partnerships to address critical research gaps in radiation oncology.

Despite more than half of all cancer patients receiving radiotherapy as part of their treatment, the complex interactions between radiation and the immune system are poorly understood. Our Center will work to improve understanding of radiation effects on the immune system (tested first in pancreas and cervical cancer) and use that knowledge to propose new radiation treatment combinations to improve the outcomes of patients with advanced cancer. We will bring together a diverse group of experts from many fields, while teaching the next generation of researchers.