Role of CD73 on peritoneal macrophages in age-associated immune dysfunction and tumor immunity

Abstract Aging is a major risk factor for cancer and many other life-threatening diseases due in part to a wide range of age-associated immune dysfunctions. In the context of cancer, chronic, low-grade inflammation seen with aging is thought to contribute to cellular transformation and tumorigenesis. Tissue resident macrophages (TRM) are key innate immune regulators of the inflammatory milieu in all tissues, and studies from our laboratory have shown that expression of the 5’-ectonucleotidase CD73 on macrophages suppresses inflammatory responses and promotes the resolution of tissue inflammation in the lung and peritoneum. However, the role of CD73 on TRM in modulating inflammation during aging or how age-associated changes in CD73 on TRM contribute to cancer development are not known. We have found that large peritoneal macrophages from aged mice (18+ months) show significantly increased levels of surface CD73 compared to young mice (<4 months). To test the role of CD73 in regulating inflammation in vivo, we utilized mouse models of ovarian cancer and peritonitis. Our preliminary studies suggest that blocking CD73 in aged mice reduces LPS-mediated production of TNF-a in vivo and ex vivo when compared to young mice. In addition, we found that treatment of ID8-Def29/Vegf-a tumor-bearing mice with anti-CD73 monoclonal antibody significantly prolongs the survival of aged mice compared to young mice. In ongoing experiments, we are utilizing conditional deletion approaches to address the role of CD73 specifically on macrophages in these models. Results from this study will provide insight into the immunoregulatory role of CD73 on TRM during aging and cancer, and will help refine therapeutic approaches targeting CD73 in cancer immunotherapy. Supported by NIH grants T32 AI007496 and R01 AI114554.