Glut1+ cancer associated fibroblasts enforce a metabolic barrier to tumor T cell infiltration

项目总结

PROJECT SUMMARY T cell trafficking to tumors represents a critical process in the tumor immunity cycle. However, many tumors can recruit T cells to the tumor, but these T cells are restricted to the tumor margin and fail to infiltrate to the inner tumor parenchyma. The resulting “immune excluded” tumors are poorly responsive to T cell targeting immunotherapy treatments. Cancer Associated Fibroblasts (CAFs) are the major stromal cells in many tumors and may restrict T cell infiltration by secreting dense extracellular matrix that physically blocks the movement of lymphocytes into tumors. Recent studies in carcinomas show that CAFs are highly heterogenous in expression profiles and their functional role in tumors. However, the role of CAFs in soft-tissue sarcoma tumors has not been defined. Furthermore, little is known about which specific populations of CAFs are mediators of T cell exclusion and if mechanisms other than extracellular matrix deposition contribute to the exclusion of T cells. The proposed research project will address the hypothesis that CAFs block T cell infiltration at the tumor margin through their altered glucose metabolism and blocking CAFs glucose metabolism may promote cytotoxic T cell infiltration into the tumor mass. In this line, inhibiting CAF glucose metabolism in combination with immune-based therapies may further promote a cytotoxic anti-tumor response. Using a model of immune excluded soft-tissue sarcoma developed in our lab, we will deplete the tumors of the glucose addicted CAFs using aSMA-TK mice. In complementary experiments, glucose metabolism of CAFs will be disrupted using conditional deletion of the glucose transporter, GLUT1, to determine if blocking CAF glucose metabolism can restore T cell infiltration. The combination GLUT1 inhibition and anti-PD-1 blockade will be evaluated for its effects on tumor growth and the effects on the infiltration and activation status of the cytotoxic T cells with respect to tumor cells and CAFs through a highly multiplexed spatial proteomics approach. These experiments will highlight novel mechanisms of CAFs in immune exclusion and immune escape. These findings will highlight strategies to target pro-tumor CAFs to promote immune infiltration to ultimately sensitize tumors to immunotherapies.