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

基本信息

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
项目类别：
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

项目摘要

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（来自家长资助 R01CA247500）癌症免疫疗法的目标是利用免疫系统消灭癌症患者的肿瘤二。方法已在临床上取得成功（i）“检查点阻断”疗法利用阻断抗体来治疗。抑制性细胞表面受体或其配体（CTLA4、PD-1/PD-L1）以消耗瘤内调节性 T 细胞 (Treg) 或克服 CD8+ T 中出现的反应低下状态，称为“疲惫”或“功能障碍” 然而，只有一小部分患者获得完全缓解，这是一个问题。 (二) T细胞表达识别肿瘤抗原的嵌合抗原受体（CAR）对抗肿瘤效果出人意料地有效造血系统癌症，例如 B-CLL（B 细胞慢性淋巴细胞白血病），但对实体瘤，显然是因为它们变得“疲惫不堪”，就像正常的 CD8 T 细胞对标准反应一样肽/MHC 配体。在这里，我们提出了一种提高 CAR T 细胞攻击实体瘤有效性的新策略。几年前，我们发现 TET（十十一易位）酶是使用分子的双加氧酶氧气、α-酮戊二酸 (αKG) 和还原铁 (Fe2+) 氧化 5-甲基胞嘧啶 (5mC) 的甲基 DNA 转化为 5-羟甲基胞嘧啶 (5hmC) 和其他氧化甲基胞嘧啶，它们都是我们在小鼠模型中证明，TET 缺陷会导致细胞谱系倾斜。许多细胞类型中信号依赖性细胞增殖的规范化和增强会损害 T 的功能；通过降低 Foxp3 表达的稳定性并提高脾 CD4+ 的能力来调节 Treg 细胞；和 CD8+ 肿瘤浸润 T 细胞 (TIL) 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并偏向中央记忆表型，两者都是稳态的骨髓细胞中 Tet2 缺乏导致免疫抑制减弱肿瘤相关巨噬细胞和骨髓源性抑制细胞，产生更有效的肿瘤肿瘤浸润 T 细胞的消退；TET2 缺陷的 CAR T 细胞促进完全缓解给予慢性淋巴细胞白血病患者。在这里，我们将检验肿瘤浸润 CD8+ T 细胞 (CD8 TIL) 中 TET 功能丧失改善的假设肿瘤排斥。在目标 1 中，我们将研究 TET 蛋白在 CD8+ TIL 的扩增和功能中的作用。代谢物 L-2-羟基戊二酸 (L-2HG) 是 TET 酶和其他 αKG- 和 Fe2+- 的有效抑制剂依赖双加氧酶的 L-2HG 水平通常通过 L-酶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 消耗或 L-2HG 预处理的影响。在目标 3 中，我们将描述 CD8+ TIL 中涉及 TET 酶的转录网络。