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

项目总结 T细胞向肿瘤的转运是肿瘤免疫循环中的一个关键过程。然而，许多肿瘤 可以将T细胞招募到肿瘤中，但这些T细胞仅限于肿瘤边缘，无法渗透到 肿瘤内实质。由此产生的“免疫排斥”肿瘤对T细胞靶向的反应很差 免疫治疗。肿瘤相关成纤维细胞(CAF)是许多肿瘤的主要基质细胞 并可能通过分泌致密的细胞外基质来限制T细胞的渗透，从而物理上阻止T细胞的运动 淋巴细胞转化为肿瘤。最近对癌症的研究表明，CAF在表达上高度异质性。 简介及其在肿瘤中的功能作用。然而，CAF在软组织肉瘤中的作用尚未见报道。 已经被定义了。此外，几乎不知道哪些特定的CAF群体是T细胞的介体 细胞外基质沉积以外的排斥和IF机制有助于T细胞的排斥。 拟议的研究项目将解决CAF阻止肿瘤处T细胞渗透的假设 边缘通过改变糖代谢和阻断CAF的糖代谢可能促进 肿瘤组织中有细胞毒性T细胞的浸润。在这条线上，联合抑制CAF的葡萄糖代谢 基于免疫的治疗可能进一步促进细胞毒性抗肿瘤反应。使用一种免疫模型 排除我们实验室发展的软组织肉瘤，我们将消耗葡萄糖成瘾的CAF的肿瘤。 使用ASMA-TK小鼠。在补充性实验中，CAF的葡萄糖代谢将被干扰 有条件地删除葡萄糖转运蛋白GLUT1，以确定阻断CAF葡萄糖代谢是否可以 恢复T细胞的浸润。GLUT1抑制和抗PD-1阻断的联合应用将评估其 对肿瘤生长的影响及对细胞毒T细胞的侵袭和活化状态的影响 通过高度多元化的空间蛋白质组学方法研究肿瘤细胞和CAF。这些实验 将重点介绍CAF在免疫排斥和免疫逃逸方面的新机制。这些发现将 强调以促肿瘤CAF为靶点的策略，以促进免疫渗透，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.