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.

项目概要 T 细胞向肿瘤的运输是肿瘤免疫周期中的一个关键过程。然而，许多肿瘤。 可以将T细胞招募到肿瘤，但这些T细胞仅限于肿瘤边缘，无法浸润到肿瘤 由此产生的“免疫排斥”肿瘤对 T 细胞靶向反应较差。 癌症相关成纤维细胞（CAF）是许多肿瘤中的主要基质细胞。 并可能通过分泌致密的细胞外基质来限制 T 细胞浸润，该基质物理上阻止 T 细胞的运动 最近的癌症研究表明，CAF 的表达具有高度异质性。 然而，CAF 在软组织肉瘤中的作用尚未得到证实。 此外，对于哪些特定的 CAF 群体是 T 细胞的介质知之甚少 排除和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 CAF 阻止肿瘤 T 细胞浸润的假设 通过改变葡萄糖代谢和阻断CAF，葡萄糖代谢可能会促进 细胞毒性 T 细胞浸润到肿瘤块中，与抑制 CAF 葡萄糖代谢相结合。 使用免疫模型，基于免疫的疗法可能会进一步促进细胞毒性抗肿瘤反应。 排除我们实验室开发的软组织肉瘤，我们将消除葡萄糖成瘾的 CAF 的肿瘤 在补充实验中，使用 aSMA-TK 小鼠，CAF 的葡萄糖代谢将被破坏。 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 将评估 GLUT1 抑制和抗 PD-1 阻断组合的恢复 T 细胞浸润的效果。 对肿瘤生长的影响以及对细胞毒性T细胞浸润和活化状态的影响 这些实验通过高度多重空间蛋白质组学方法来研究肿瘤细胞和 CAF。 这些发现将突出 CAF 在免疫排斥和免疫逃逸中的新机制。 强调针对促肿瘤 CAF 的策略，以促进免疫浸润，最终使肿瘤对 免疫疗法。