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

Glut1癌症相关成纤维细胞增强了肿瘤T细胞浸润的代谢屏障

• 批准号: 10752508
• 负责人: Marina T Broz
• 金额: $ 4.13万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-19 至 2026-01-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752508
• 关键词: Antitumor Response; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Carcinoma; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Deposition; Exclusion; Extracellular Matrix; Fibroblasts; Glucose; Glucose Transporter; Glycolysis; Glycolysis Inhibition; Goals; Immune; Immunologic Sensitization; Immunological Models; Immunotherapy; Infiltration; Intervention; Knowledge; Lymphocyte; Malignant Fibrous Histiocytoma; Malignant Neoplasms; Mediating; Mediator; Metabolic; Metabolism; Molecular; Movement; Mus; Nutrient; PD-1 blockade; Pathway interactions; Patients; Penetration; Population; Positioning Attribute; Process; Production; Proteomics; Research; Research Project Grants; Role; SLC2A1 gene; Soft tissue sarcoma; Stromal Cells; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Tumor Escape; Tumor Immunity; Tumor-Associated Process; Tumor-infiltrating immune cells; anti-PD-1; cancer infiltrating T cells; cell motility; combinatorial; cytotoxic; efficacy evaluation; experimental study; forging; glucose metabolism; immune cell infiltrate; immune checkpoint blockade; inhibitor; insight; migration; mouse model; neoplastic cell; novel; novel therapeutic intervention; recruit; response; sarcoma; single-cell RNA sequencing; therapeutic target; trafficking; transcriptomics; treatment effect; tumor; tumor growth; tumor metabolism; tumor microenvironment

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.

项目摘要 T细胞运输到肿瘤是肿瘤免疫细胞中的关键过程。但是，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，并且未能渗入 内肿瘤实质。由此产生的“免疫排除”肿瘤对T细胞靶向的响应不佳 免疫治疗。癌症相关的成纤维细胞（CAF）是许多肿瘤中的主要基质细胞 并可能通过分泌密集的细胞外基质来限制T细胞的浸润 淋巴细胞成肿瘤。癌症的最新研究表明，CAF在表达上是高度异质的 特征及其在肿瘤中的功能作用。但是，CAF在软组织肉瘤肿瘤中的作用尚未 他被定义了。此外，对哪些特定咖啡馆的特定种群是T细胞的介体，知之甚少 排除和如果细胞外基质沉积以外的机制有助于排除T细胞。 拟议的研究项目将解决以下假设，即CAFS阻止T细胞在肿瘤处浸润 通过改变的葡萄糖代谢和阻断CAFS葡萄糖代谢的边缘可能会促进 细胞毒性T细胞浸润到肿瘤质量中。在这一行中，抑制CAF葡萄糖代谢组合 使用基于免疫的疗法可以进一步促进细胞毒性抗肿瘤反应。使用免疫模型 在我们的实验室中开发的排除软组织肉瘤，我们将部署葡萄糖上瘾CAF的肿瘤 使用ASMA-TK小鼠。在完整的实验中，CAF的葡萄糖代谢将被破坏 葡萄糖转运蛋白Glut1的条件缺失，以确定阻断CAF葡萄糖代谢是否可以 恢复T细胞浸润。将对GLUT1抑制和抗PD-1封锁的组合进行评估 对肿瘤生长的影响以及对细胞毒性T细胞浸润和激活状态的影响 通过高度多重的空间蛋白质组学方法对肿瘤细胞和CAF。这些实验 将重点介绍CAF在免疫排除和免疫逃生中的新机制。这些发现会 强调针对亲肿瘤CAF的策略，以促进免疫浸润以最终敏感的肿瘤 免疫疗法。