Description

T cell expressed miR-155 regulates the tumor microenvironment and enhances the response to immune checkpoint blockade therapy

Thomas B. Huffaker, Soh-Hyun Lee, Ruozhen Hu, Marah C. Runtsch, Margaret Alexander, Jared A. Wallace, Dane K. Larsen, Jacob Thompson, Andrew G. Ramstead, Warren P. Voth, June L. Round, Matthew A. Williams, and Ryan M. O’Connell

Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Dr. East, JMRB, Salt Lake City, UT, 84112

MicroRNA-155 (miR-155) has recently been shown to promote anti-tumor immune responses. However, its specific functions within distinct immune cell types during this process have not been clearly delineated. Using conditional knockout mice, we investigated the roles of miR-155 in two immune cell compartments, T cells and macrophages, during the immune response to syngeneic melanoma tumors. The results indicate that miR-155 expression within T cells, but not macrophages, is required to reduce tumor growth and promote interferon gamma production within the tumor microenvironment. Additionally, miR-155 expression by T cells promoted tumor associated macrophage (TAM) expression of interferon gamma inducible genes and reduced the accumulation of myeloid derived suppressor cells within tumor bearing mice. Finally, we found that blocking PD1 and CTLA4 only partially enhanced the T cell response and antitumor immunity in miR-155 T cell conditional knockout (T-CKO) mice, revealing miR-155 dependent and independent aspects of the response to immune checkpoint blockade therapy. Taken together, our findings highlight the critical role that miR-155 plays in T cells as it coordinates antitumor immunity, and suggest that its augmentation could be combined with immune checkpoint blockade to provide a superior outcome in cancer patients undergoing immunotherapy.