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: 9364857
• 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/9364857
• 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; Clinical Trials; Coculture Techniques; Cytotoxic T-Lymphocyte-Associated Protein 4; 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; Injectable; 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; Phase; Population; Proteins; Publishing; Reporting; Role; Signal Transduction; Solid; Solid Neoplasm; T-Cell Receptor; T-Lymphocyte; Testing; Thoracic Neoplasms; Transgenic Organisms; Tumor-Infiltrating Lymphocytes; Uncertainty; Up-Regulation; Xenograft Model; base; cancer immunotherapy; carcinoembryonic antigen-related cell adhesion molecules; chimeric antigen receptor; extracellular; genetic manipulation; immune checkpoint blockade; immunological synapse formation; in vitro Assay; in vivo; in vivo Model; intraperitoneal; melanoma; neoplastic cell; outcome forecast; 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).

胸部的实体肿瘤仍然是一个重大的医疗负担。肺癌仍居首位 癌症的死因。恶性胸膜间皮瘤(MPM)仍然无法治愈，预示着一种令人沮丧的 预后约为一年。一种有希望的免疫治疗方法是检查站封锁 抑制性受体(IR)，如程序性死亡1(PD1)。然而，对PD1检查站封锁的反应是 仅在20%的实体瘤患者中可见。T细胞(嵌合抗原受体)的基因修饰 (CARS和转基因T细胞受体(TCRs))不能预防PD1诱导的功能低下，支持 需要更好地了解IRS与TME的交互方式以及它们在T细胞内传递信号的方式 诱导TIL功能低下--自然发生的肿瘤浸润性淋巴细胞(TIL)和过敏性TIL 转移的，基因工程的TIL。我们以前证明了PD1检查点在异种移植中是封闭的 肺癌模型和MPM一次静脉注射可加强对侧翼肿瘤生长的控制 肿瘤反应性人体效应T细胞的剂量。然而，肿瘤的增大并不明显，肿瘤仍在继续 进步。在仔细分析了从小鼠侧翼肿瘤中分离出的TIL后，我们得出了几个结论 帮助我们理解为什么TIL的抗肿瘤功能仍然受到抑制的观察结果：1)PD1 BLOCKADE只能部分保留TIL功能，2)TIL有多个IR，除PD1上调外， 3)PD1阻断后，部分IR的表达增加。一个IR是 TIM3在TIL中上调，特别是在也接受PD1阻断的小鼠TIL中。 当我们随后对接受了一次过继转移T细胞的侧翼肿瘤荷瘤小鼠进行治疗时 静脉注射多次注射抗TIM3抗体，效果很小。这 可能是由于第二个受体CEACAM1，已被证明调节TIM3在小鼠身上的功能 T细胞。对我们自己的人类T细胞进行的流式细胞仪分析显示存在四个不同 群体：1)TIM3-/CEACAM1-，2)TIM3+/CEACAM1-，3)TIM3-/CEACAM1+，4)TIM3+/CEACAM1+。 我们推测，抗TIM3抗体不仅干扰了抑制性TIM3(即 与CEACAM1在种群#4中共表达)，但也干扰了激活的TIM3(即 在2号人群中没有CEACAM1共表达)，因此对T细胞控制肿瘤的净影响最小 成长。CEACAM1也在我们的肿瘤细胞上表达。鉴于TIM3是一个有希望的癌症靶点 关于免疫疗法，这项建议旨在阐明其功能以及它与CEACAM1的相互作用。我们建议 研究TIM3最重要的配体(AIM 1)，TIM3‘对S胞外配体识别的影响 结构域与TIM3‘S细胞内信号域对TIM3诱导的T细胞功能低下的影响 CEACAM1对人效应T细胞抗肿瘤活性的影响(目标3)。