| Description |
The immune response within the tumor microenvironment is shaped by immune cell subsets that either promote or inhibit tumor progression. Increased understanding of the biological processes through which immune cells function to eliminate cancer cells may lead to new treatments for cancer patients. microRNAs are nonprotein coding RNAs that represent a novel mechanism of immune cell regulation. We discovered that the proinflammatory microRNA-155 (miR-155) and the anti-inflammatory microRNA-146a (miR-146a) regulate T cell-mediated anti-tumor immunity to transplanted B16f10 melanomas. miR-155 promoted IFNγ expression in T cells by targeting Ship1 to reduce tumor growth while miR-146a regulated the immune response by IFNγ expressing T cells to repress the antitumor immune response. Conditional knockout of miR-155 within T cells resulted in decreased expression of IFNγ dependent genes in tumor associated macrophages (TAMs), demonstrating functional crosstalk between T cells and TAMs that required T cell expressed miR-155. Sequencing of tumor infiltrating T cells from miR-155 T cell conditional knockout mice revealed defects in the expression of effector and activation genes including IFNγ, granzyme B, perforin, Tnf, and CD62l. Interestingly, miR-155 was not required for the response to immune checkpoint blocking (ICB) antibodies. miR-155 deficient T cells functionally expressed IFNγ at near Wt levels and recovered the expression of granzyme B, perforin, and CD62l when given ICB. Many of the targets of miR-155 that were derepressed in knockout cells were recovered back toward Wt levels in mice treated with ICB, indicating a potential overlap in the pathways regulated by miR-155 and ICB. Finally, we discovered a novel DNA regulatory element in tumor infiltrating macrophages that upregulates an important metabolic enzyme, Nampt, in response to IFNγ via a Stat1 dependent mechanism. We termed this region Nampt regulatory element 1 (NRE1). Via CRISPR-Cas9-mediated deletion of this region, we have implicated Nampt in the regulation of the chemokine receptor CCR1 and future experiments with NRE1 floxed mice will focus on the role of this region in regulating anti-tumor immune responses. |
