The role of TIM3 and CEACAM1 in anti-tumor function of human effector T cells

TIM3和CEACAM1在人效应T细胞抗肿瘤功能中的作用

• 批准号: 9978734
• 负责人: Edmund K. Moon
• 金额: $ 36.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978734
• 关键词: Adoptive Transfer; Affect; Antibodies; Binding; Biological Assay; Blocking Antibodies; CD8B1 gene; CTLA4 gene; Cancer Etiology; Carcinoembryonic Antigen; Cell Adhesion; Cell Communication; Cell Surface Receptors; Cell physiology; Cessation of life; Coculture Techniques; Data; Dose; Functional disorder; Galactose Binding Lectin; Genetic; Genetic Engineering; Goals; HMGB1 gene; Healthcare; Human; Human Activities; ITIM; Immunoglobulins; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Intravenous; Ligand Binding; Ligands; Light; Literature; Lymphocyte Function; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant neoplasm of lung; Mesothelioma; Methods; Minor; Minority; Modeling; Modification; Mucins; Mus; Patients; Population; Proteins; Publishing; Reporting; Role; Signal Transduction; Solid; Solid Neoplasm; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Thoracic Neoplasms; Transgenic Organisms; Tumor-Infiltrating Lymphocytes; Uncertainty; Up-Regulation; Xenograft Model; anti-CTLA4; base; cancer immunotherapy; carcinoembryonic antigen-related cell adhesion molecules; chimeric antigen receptor; early phase clinical trial; effector T cell; extracellular; genetic manipulation; human model; immune checkpoint blockade; immune checkpoint blockers; immunological synapse formation; in vitro Assay; in vivo; in vivo Model; intraperitoneal; melanoma; neoplastic cell; outcome forecast; preservation; programmed cell death protein 1; receptor; response; success; synaptogenesis; tumor; tumor growth; tumor microenvironment; tumor xenograft

Solid tumors of the thorax continue to be a significant healthcare burden. Lung cancer remains the leading cause of cancer death. Malignant pleural mesothelioma (MPM) is still without cure and portends a dismal prognosis of about one year. One promising immunotherapeutic approach has been checkpoint blockade of inhibitory receptors (IRs), like programmed death 1 (PD1). However, response to PD1 checkpoint blockade is seen only in 20% of patients with solid tumors. Genetic modification of T cells (with chimeric antigen receptors (CARs) and transgenic T cell receptors (TCRs)) does not prevent the hypofunction induced by PD1, supporting the need to better understand the way IRs interact with the TME and the way they signal within T cells to induce TIL hypofunction—in both naturally occurring tumor infiltrating lymphocytes (TILs) and adoptively transferred, genetically engineered TILs. We previously showed that PD1 checkpoint blockade in xenograft models of lung cancer and MPM is able to augment the control of flank tumor growth after one intravenous dose of tumor-reactive human effector T cells. However, the augmentation is modest and tumors continue to progress. Upon closer analysis of the TILs isolated from the flank tumors of the mice, we made a few observations that helped us understand why the TILs were still suppressed in their anti-tumor function: 1) PD1 blockade was able to only partially preserve TIL function, 2) TILs had multiple IRs, other than PD1 upregulated, 3) some of these IRs seemed to increase in expression in response to PD1 blockade. One IR that was upregulated in the TILs, particularly in the TILs from the mice that also received PD1 blockade, was TIM3. When we subsequently treated flank tumor bearing mice that were given one adoptive transfer of T cells intravenously with repeated intraperitoneal doses of anti-TIM3 antibody, a very minor effect was seen. This may be due to a second receptor, CEACAM1, that has been shown to regulate the function of TIM3 on murine T cells. Flow cytometric analysis of our own human T cells revealed the presence of four difference populations: 1) TIM3-/CEACAM1-, 2) TIM3+/CEACAM1-, 3) TIM3-/CEACAM1+, and 4) TIM3+/CEACAM1+. We presumed that the anti-TIM3 antibody interfered with not only the inhibitory TIM3 (i.e. that which was coexpressed with CEACAM1 in population #4) but also interfered with the activating TIM3 (i.e. that which had no CEACAM1 coexpression in population #2), hence resulting in a net minimal effect on T cell control of tumor growth. CEACAM1 is also expressed on our tumor cells. In light of TIM3 being a promising target in cancer immunotherapy, this proposal aims to clarify its function as well as its interplay with CEACAM1. We propose to investigate the most important ligands for TIM3 (Aim 1), the impact of TIM3’s extracellular ligand-recognition domain vs. TIM3’s intracellular signaling domains on TIM3-induced T cell hypofunction (Aim 2), the impact of CEACAM1 on the anti-tumor activity of human effector T cells (Aim 3).

胸部的实体瘤仍然是重大的医疗负担。肺癌仍然是领先的 癌症死亡的原因。恶性胸膜间皮瘤（MPM）仍然无法治愈，预示着令人沮丧的 预后约一年。一种有希望的免疫治疗方法是检查点的封锁 抑制受体（IRS），例如编程死亡1（PD1）。但是，对PD1检查点封锁的响应是 仅参见20％的实体瘤患者。 T细胞的遗传修饰（用嵌合抗原受体 （CARS）和转基因T细胞受体（TCRS）并不能阻止PD1诱导的功能障碍，从而支持 需要更好地了解IRS与TME互动的方式以及它们在T细胞中发出信号的方式 诱导截至功能障碍 - 在天然存在的肿瘤浸润（TIL）和自适应 转移，一般设计的tils。我们先前证明了异种移植物中的PD1检查点阻滞 肺癌和MPM的模型能够增强一次静脉注射后侧面肿瘤生长的控制 肿瘤反应性人体效应T细胞的剂量。但是，增强是适中的，肿瘤继续 进步。在对从小鼠侧面肿瘤分离的til进行仔细分析后，我们做了一些 有助于我们理解为什么TIL在其抗肿瘤功能中仍然被抑制的观察结果：1）PD1 封锁只能部分保留til函数，2）TIL具有多个IRS，除了更新PD1以外， 3）这些IR中的一些似乎在响应PD1封锁的响应中增加了表达。一个IR是 TIM3在TIL中被上调，特别是在也受到PD1封锁的小鼠的til中。 当我们随后处理侧面肿瘤的轴承小鼠时，该肿瘤被带到了T细胞的转移 静脉内静脉内静脉内剂量的抗TIM3抗体静脉注射，观察到非常小的作用。 可能是由于第二个接收器CEACAM1，已证明可以调节Tim3在鼠上的功能 T细胞。我们自己的人类T细胞的流式细胞仪分析揭示了存在四种差异 种群：1）TIM3-/CECAM1-，2）TIM3+/CECAM1-，3）TIM3-/CECAM1+，4）TIM3+/CECACAM1+。 我们提出的是，抗TIM3抗体不仅会干扰抑制性tim3（即 在人口＃4中与CEACAM1共表达），但也干扰了激活的TIM3（即 人口＃2中没有CEACAM1共表达），因此导致对肿瘤的T细胞控制的净最小影响 生长。 CEACAM1也在我们的肿瘤细胞上表达。鉴于TIM3是癌症的有希望的目标 免疫疗法，该建议旨在阐明其功能以及与CEACAM1的相互作用。我们建议 调查TIM3最重要的配体（AIM 1），TIM3的细胞外配体识别的影响 域与TIM3在TIM3诱导的T细胞功能下的细胞内信号传导域（AIM 2），其影响 CEACAM1对人类效应T细胞的抗肿瘤活性（AIM 3）。