Exploring the potential of TET inhibition in cancer immunotherapy

探索 TET 抑制在癌症免疫治疗中的潜力

• 批准号: 10819075
• 负责人: Anjana Rao
• 金额: $ 10.46万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10819075
• 关键词: Antibodies; Blocking Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cancer Patient; Cell Lineage; Cell Proliferation; Cell Surface Receptors; Cells; Chronic Lymphocytic Leukemia; Clinic; Cytotoxic T-Lymphocytes; DNA; Development; Dioxygenases; Disease remission; Effectiveness; Enzymes; FOXP3 gene; Functional disorder; Genetic Transcription; Goals; Hematologic Neoplasms; Human; Immune system; Immunosuppression; Impairment; Infiltration; Iron; Ligands; Malignant Neoplasms; Memory; Molecular; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Oxidoreductase; Oxygen; PD-1/PD-L1; Pathway interactions; Patients; Peptides; Phenotype; Protein translocation; Regulatory T-Lymphocyte; Role; Signal Transduction; Solid Neoplasm; Specific qualifier value; T cell infiltration; T-Lymphocyte; Testing; Tumor Antigens; Tumor Promotion; Tumor-associated macrophages; Virus Diseases; alpha ketoglutarate; anti-cancer; cancer cell; cancer immunotherapy; cancer infiltrating T cells; cancer therapy; cell type; chimeric antigen receptor; chimeric antigen receptor T cells; chronic lymphocytic leukemia cell; demethylation; exhaust; exhaustion; immune checkpoint blockade; improved; inhibitor; loss of function; methyl group; mouse model; parent grant; patient subsets; prevent; protein function; receptor; response; tumor

Abstract (From Parent Grant R01CA247500) The goal of cancer immunotherapy is to harness the immune system to destroy tumors in cancer patients. Two approaches have been successful in the clinic. (i) “Checkpoint blockade” therapies utilize blocking antibodies to inhibitory cell surface receptors or their ligands (CTLA4, PD-1/PD-L1) to deplete intratumoral regulatory T cells (Tregs) or to overcome a hyporesponsive state, termed “exhaustion” or “dysfunction”, that develops in CD8+ T cells that infiltrate solid tumors. However, only a subset of patients achieve complete remission, a problem that can potentially be countered by using combinations of antibodies to multiple inhibitory receptors. (ii) T cells expressing chimeric antigen receptors (CARs) that recognize tumor antigens are remarkably effective against hematopoietic cancers such as B-CLL (B cell chronic lymphocytic leukemia), but are not as effective against solid tumors, apparently because they become “exhausted” much like normal CD8 T cells responsive to standard peptide/MHC ligands. Here we propose a new strategy for increasing the effectiveness of CAR T cells attacking solid tumors. Some years ago, we discovered that TET (Ten-Eleven Translocation) enzymes are dioxygenases that use molecular oxygen, α-ketoglutarate (αKG) and reduced iron (Fe2+) to oxidize the methyl group of 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC) and additional oxidized methylcytosines that are all intermediates in DNA demethylation. We have shown in mouse models that TET deficiency results in skewed cell lineage specification and enhanced signal-dependent cell proliferation in many cell types; impairs the function of T regulatory (Treg) cells by decreasing the stability of Foxp3 expression; and improves the ability of splenic CD4+ and CD8+ tumor-infiltrating T cells (TILs) to promote tumor regression. Moreover, Tet2-deficient mouse CD8+ T cells displayed cell-intrinsic expansion and skewing towards a central memory phenotype, both homeostatically and in response to viral infection; Tet2 deficiency in myeloid cells resulted in decreased immunosuppression by tumor-associated macrophages and myeloid-derived suppressive cells, resulting in more effective tumor regression by tumor-infiltrating T cells; and TET2-deficient CAR T cells promoted complete remission when administered to a patient with chronic lymphocytic leukemia. Here we will test the hypothesis that TET loss-of-function in tumor-infiltrating CD8+ T cells (CD8 TILs) improves tumor rejection. In Aim 1, we will examine the role of TET proteins in the expansion and function of CD8+ TILs. The metabolite L-2-hydroxyglutarate (L-2HG) is a potent inhibitor of TET enzymes and other αKG- and Fe2+- dependent dioxygenases. L-2HG levels are normally maintained at very low levels in cells by the enzyme L- 2HG dehydrogenase (L2HGDH). In Aim 2, we will assess the effects of L2HGDH depletion or L-2HG pretreat- ment on CAR TILs. In Aim 3, we will delineate the transcriptional networks involving TET enzymes in CD8+ TILs.

摘要（来自母基金R01CA247500） 癌症免疫治疗的目标是利用免疫系统摧毁癌症患者的肿瘤。两 这些方法在临床上是成功的。(i)"检查点阻断"疗法利用阻断抗体， 抑制性细胞表面受体或其配体（CTLA 4，PD-1/PD-L1）以耗尽肿瘤内调节性T细胞 或克服在CD8 + T细胞中发展的低反应状态，称为"衰竭"或"功能障碍"， 浸润实体瘤的细胞然而，只有一部分患者达到完全缓解，这是一个问题， 可以通过使用针对多种抑制性受体的抗体的组合来潜在地对抗。(ii)t细胞 表达识别肿瘤抗原的嵌合抗原受体（CAR）对抗肿瘤非常有效， 造血系统癌症，如B-CLL（B细胞慢性淋巴细胞白血病），但不能有效对抗 实体瘤，显然是因为它们变得"耗尽"，就像正常的CD8 T细胞对标准的免疫应答一样。 肽/MHC配体。 在这里，我们提出了一种新的策略来提高CAR T细胞攻击实体瘤的有效性。一些 多年前，我们发现泰特（十-十一易位）酶是双加氧酶， 氧、α-酮戊二酸（α KG）和还原铁（Fe 2+）氧化5-甲基胞嘧啶（5mC）的甲基， DNA转化为5-羟甲基胞嘧啶（5hmC）和另外的氧化甲基胞嘧啶，它们都是 DNA去甲基化我们在小鼠模型中发现，泰特缺乏导致细胞谱系偏斜 在许多细胞类型中的特异性和增强的信号依赖性细胞增殖;损害T细胞的功能 通过降低Foxp3表达的稳定性来抑制调节性（Treg）细胞;并提高脾CD4 + T细胞的能力。 和CD8+肿瘤浸润性T细胞（TIL）以促进肿瘤消退。此外，Tet2缺陷小鼠CD8 + T细胞 细胞表现出细胞内在的扩张和向中央记忆表型倾斜，两者都是稳态的 和对病毒感染的反应;髓系细胞中Tet2缺乏导致免疫抑制降低， 肿瘤相关巨噬细胞和骨髓源性抑制细胞，导致更有效的肿瘤 肿瘤浸润性T细胞的消退; TET2缺陷型CAR T细胞促进完全缓解， 给慢性淋巴细胞性白血病患者服用。 在这里，我们将检验肿瘤浸润性CD8 + T细胞（CD8 TIL）中的泰特功能丧失改善肿瘤浸润性CD8 + T细胞（CD8 TIL）的假设。 肿瘤排斥在目标1中，我们将研究泰特蛋白在CD8 + TIL的扩增和功能中的作用。 代谢产物L-2-羟基戊二酸（L-2HG）是泰特酶和其他α KG-和Fe2 +-的强效抑制剂 依赖性双加氧酶。L-2HG水平通常通过酶L-2HG在细胞中维持在非常低的水平。 2HG脱氢酶（L2HGDH）。在目标2中，我们将评估L2HGDH耗竭或L-2HG预处理的影响。 在汽车TILs上。在目标3中，我们将描述涉及泰特酶在CD8 + TIL中的转录网络。