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：
10665608
负责人：
Anjana Rao
金额：
$ 49.26万
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/10665608
关键词：
Alleles Antibodies Antigens Antitumor Response Biological Process Blocking Antibodies CAR T cell therapy CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cancer Patient Cell Differentiation process Cell Lineage Cell Proliferation Cell Surface Receptors Cell physiology Cells Chronic Chronic Lymphocytic Leukemia Clinic Cytotoxic T-Lymphocytes DNA Data Development Dioxygenases Disease remission Effectiveness Enzymes Exhibits Exposure to FOXP3 gene Functional disorder Genetic Transcription Goals Hematologic Neoplasms Human Immune Immune response Immune system Immunosuppression Impairment Infiltration Iron Ligands Malignant Neoplasms Memory Molecular Mus Mutation Myeloid Cells Myeloid-derived suppressor cells Oxidases Oxidoreductase Oxygen PD-1/PD-L1 Paper Pathway interactions Patients Peptides Phenotype Population Production Proliferating Protein translocation Regulatory T-Lymphocyte Rejuvenation Role Signal Pathway Signal Transduction Solid Neoplasm Specific qualifier value T cell infiltration T-Lymphocyte TCF Transcription Factor Testing Time Transplantation Tumor Antigens Tumor Escape Tumor Promotion Tumor-associated macrophages Up-Regulation Virus Diseases alpha ketoglutarate anti-PD-1 anti-PD-L1 anti-cancer cancer cell cancer immunotherapy cancer infiltrating T cells cancer therapy cell type chimeric antigen receptor chimeric antigen receptor T cells chronic infection chronic lymphocytic leukemia cell cytokine demethylation exhaust exhaustion genome-wide human model immune checkpoint blockade improved inhibitor innovation loss of function methyl group mouse model patient subsets prevent programmed cell death ligand 1 programmed cell death protein 1 protein function receptor response restraint stem success tumor tumor microenvironment

项目摘要

Abstract. 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.

抽象的。癌症免疫疗法的目的是利用免疫系统破坏癌症的肿瘤患者。在诊所中，两种方法已经成功。（i）“检查点封锁”疗法利用阻塞对抑制性细胞表面受体或其配体（CTLA4，PD-1/PD-L1）的抗体调节性T细胞（TREG）或克服低反应状态，称为“疲惫”或“功能障碍”，在浸润实体瘤的CD8+ T细胞中发展。但是，只有一部分患者完成缓解，可以通过使用多种抑制性抗体的组合来解决这个问题受体。（ii）表达识别肿瘤抗原的嵌合抗原受体（CAR）的T细胞是非常有效地针对造血癌（B细胞慢性淋巴细胞性白血病）等造血癌，但对实体瘤的有效程度不那么有效，显然是因为它们变得像普通CD8一样“筋疲力尽” T细胞对标准肽/MHC配体有反应。在这里，我们提出了一种新的策略，以提高攻击实体瘤的CAR T细胞的有效性。一些几年前，我们发现TET（十个易位）酶是使用分子的双氧酶氧，α-酮戊二酸（αkg）和铁（Fe2+）降低到氧化物中5-甲基胞嘧啶（5MC）的甲基甲基（5MC） DNA至5-羟基甲基胞嘧啶（5HMC）和其他都是中间体 DNA脱甲基化。我们在鼠标模型中显示了TET缺乏导致细胞谱系偏斜在许多细胞类型中的规范和增强的信号依赖性细胞增殖；损害t的功能通过降低FOXP3表达的稳定性，调节性（Treg）细胞；并提高脾CD4+的能力和CD8+肿瘤浸润的T细胞（TIL）以促进肿瘤消退。此外，TET2缺陷鼠标CD8+ T 细胞显示细胞中心的扩展，并偏向中央记忆表型，这两者都稳态并响应病毒感染；髓样细胞中的TET2缺乏导致免疫抑制减少与肿瘤相关的巨噬细胞和髓样衍生的抑制细胞，导致更有效的肿瘤通过肿瘤浸润的T细胞回归；当Tet2缺乏型汽车T细胞促进了完全缓解给予患有慢性淋巴细胞性白血病的患者。在这里，我们将检验以下假设：肿瘤浸润CD8+ T细胞（CD8 TILS）的功能丧失可改善肿瘤排斥。在AIM 1中，我们将研究TET蛋白在CD8+ TIL的扩展和功能中的作用。代谢产物L-2-羟基戊二酸（L-2HG）是TET酶和其他αkg-和Fe2+ - 的潜在抑制剂依赖性双氧酶。通过酶L-通常将L-2HG水平保持在细胞中非常低的水平 2HG脱氢酶（L2HGDH）。在AIM 2中，我们将评估L2HGDH耗竭或L-2HG预处理的影响 - 提及汽车。在AIM 3中，我们将描绘CD8+ TIL中涉及TET酶的转录网络。