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

项目摘要 T细胞向肿瘤的运输代表了肿瘤免疫循环中的关键过程。然而，许多肿瘤 可以将T细胞募集到肿瘤中，但这些T细胞仅限于肿瘤边缘，无法浸润到肿瘤边缘。 内部肿瘤实质。由此产生的“免疫排斥”肿瘤对T细胞靶向反应不良 免疫治疗癌相关成纤维细胞（CAFs）是多种肿瘤的主要间质细胞 并可能通过分泌致密的细胞外基质来限制T细胞浸润，所述细胞外基质物理性地阻断T细胞的运动。 淋巴细胞进入肿瘤。最近的研究表明，在肿瘤中CAFs的表达是高度异质性的， 特征及其在肿瘤中的功能作用。然而，CAFs在软组织肉瘤肿瘤中的作用还没有被证实。 被定义。此外，关于哪些特定的CAF群体是T细胞介导剂， 排除，以及是否细胞外基质沉积以外的机制有助于T细胞的排除。 拟议的研究项目将解决CAFs阻断肿瘤处T细胞浸润的假设 通过改变葡萄糖代谢和阻断CAFs葡萄糖代谢， 细胞毒性T细胞浸润到肿瘤块中。在这条线上，抑制CAF葡萄糖代谢的组合 与基于免疫的疗法结合可进一步促进细胞毒性抗肿瘤应答。使用免疫模型 排除我们实验室发展的软组织肉瘤，我们将去除葡萄糖依赖的CAFs的肿瘤 使用aSMA-TK小鼠。在补充实验中，CAF的葡萄糖代谢将被破坏， 条件性删除葡萄糖转运蛋白GLUT 1，以确定阻断CAF葡萄糖代谢是否可以 恢复T细胞浸润。将评价GLUT 1抑制和抗PD-1阻断的组合的 对肿瘤生长的影响以及对细胞毒性T细胞的浸润和活化状态的影响， 通过高度多重空间蛋白质组学方法，这些实验 将突出CAF在免疫排斥和免疫逃逸中的新机制。这些发现将 突出了靶向促肿瘤CAF以促进免疫浸润从而最终使肿瘤对 免疫疗法

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.