Mechanisms of PD-1 and Tim-3 crosstalk in tumor-infiltrating lymphocytes

肿瘤浸润淋巴细胞中 PD-1 和 Tim-3 串扰的机制

• 批准号: 10745167
• 负责人: Robert L. Ferris
• 金额: $ 54.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745167
• 关键词: Ablation; Adoptive Cell Transfers; Attention; Autoimmunity; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cell physiology; Cells; Clinical; Clinical Trials; Data; Defect; Development; Equilibrium; Funding; Generations; Growth; Head and Neck Cancer; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunotherapy; In complete remission; Infection; Knock-out; Ligands; Logic; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Modality; Modeling; Molecular Profiling; Monoclonal Antibodies; Mus; Organ; Outcome; PD-1 blockade; PD-1 pathway; PD-1/PD-L1; PD-L1 blockade; Patients; Peripheral; Phenotype; Proteins; Publishing; Regulatory T-Lymphocyte; Role; Sea; Signal Transduction; Solid Neoplasm; T cell infiltration; T cell receptor repertoire sequencing; T cell therapy; T-Cell Depletion; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Translations; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Work; cancer therapy; cancer type; cell type; checkpoint therapy; exhaust; exhaustion; immune checkpoint blockade; improved; in vivo; inhibitor; mouse model; neoantigens; neoplasm immunotherapy; novel; novel strategies; programmed cell death protein 1; response; restraint; success; synergism; targeted treatment; trafficking; tumor; tumor microenvironment

PROJECT SUMMARY The past twenty years have seen a sea change in the treatment of many types of cancer, with immunotherapy- based approaches, including checkpoint blockade and adoptive cell therapy, yielding remarkable results in some patients. The inability, thus far, to achieve more complete responses in more patients has set off a widespread effort to identify novel targets for improving rates and duration of response, either as single agents or together with first-generation immunotherapies, like PD-1/PD-L1 blockade. One of the second-generation checkpoint targets that has attracted attention from many groups, including our own, is the protein Tim-3. Thus far, mAb’s targeting Tim-3 have under-performed in clinical trials for solid tumors, likely due in part to the fact that while Tim-3 is expressed at high levels on exhausted T cells, it is not expressed on the TpEx cells. Obtaining a better understanding of Tim-3 function in these various cell types may lead to more selective and efficacious Tim3- targeting therapies, either as single agents or, critically, in combination with PD-1 pathway blockade. Work from our groups and others have revealed that Tim-3 appears to be particularly important for the suppressive function of regulatory T cells (Treg) that are present in high numbers in tumors, in particular “effector” Treg (eTreg), which are a particularly suppressive subset of Treg. These cells are enriched within solid tumors, relative to their proportions in normal peripheral tissues, suggesting that they could be attractive targets for more specific augmentation of immune responses within tumors. Since a significant proportion of Treg express Tim- 3, and the function of this molecule in vivo is still being elucidated, we generated a knockout model to study Tim- 3 on these cells. Thus, we found that inducible Treg-specific Tim-3 deletion results in a dramatic decrease in both the growth of syngeneic tumors and the number of Treg infiltrating those tumors. However, Treg-specific Tim-3 deletion did not detectably impact Treg development or immune tolerance under homeostatic conditions. Based on published and preliminary data, we hypothesize that Tim-3 is a critical regulator of effector Treg in the tumor microenvironment. We will test this hypothesis with three Specific Aims. In Aim 1, we will determine why there are fewer eTreg in the tumors of mice with Treg-specific Tim-3 KO. In Aim 2, we will define the effects of loss of Treg Tim-3 on the tumor microenvironment. Finally, in Aim 3, we will determine how the loss of Tim-3 on Treg impacts the response to PD-1 checkpoint blockade, in both mouse models, with an extension toward the role of the interaction in the response to PD-1 blockade therapy in patients with head and neck cancer. Together, these studies will provide the basis for more rational translation of Tim-3 as a target in the treatment of solid tumors, in the context of existing checkpoint targets like PD-1. As such, these studies represent a logical extension of work carried out in the previous cycle of this funded project.

项目概要 在过去的二十年里，许多类型的癌症的治疗发生了翻天覆地的变化，免疫疗法—— 基于的方法，包括检查点封锁和过继性细胞疗法，在一些方面产生了显着的效果 迄今为止，无法在更多患者中获得更完全的缓解，这引发了广泛的关注。 努力确定新的目标，以提高反应率和持续时间，无论是作为单一药物还是共同使用 与第一代免疫疗法一样，PD-1/PD-L1阻断是第二代检查点之一。 迄今为止，mAb 的蛋白质 Tim-3 已引起包括我们自己在内的许多团体的关注。 靶向 Tim-3 在实体瘤临床试验中表现不佳，部分原因可能是 Tim-3 在耗尽的 T 细胞上高水平表达，但在 TpEx 细胞上不表达。 了解 Tim-3 在这些不同细胞类型中的功能可能会导致更具选择性和更有效的 Tim3- 靶向治疗，可以作为单一药物，也可以与 PD-1 通路阻断剂联合使用。 我们的团队和其他人的工作表明，Tim-3 似乎对于 肿瘤中大量存在的调节性 T 细胞 (Treg) 的抑制功能，特别是“效应细胞” Treg (eTreg) 是 Treg 的一个特别抑制性的子集，这些细胞在实体瘤中富集。 相对于它们在正常外周组织中的比例，这表明它们可能成为更多人的有吸引力的目标 肿瘤内免疫反应的特异性增强，因为很大一部分 Treg 表达 Tim-。 3，并且该分子在体内的功能仍在阐明中，我们生成了敲除模型来研究Tim- 3 因此，我们发现诱导性 Treg 特异性 Tim-3 缺失会导致 Treg 的急剧减少。 同源肿瘤的生长和浸润这些肿瘤的 Treg 数量。 Tim-3 缺失并未明显影响稳态条件下 Treg 的发育或免疫耐受。 根据已发表的初步数据，我们发现 Tim-3 是效应 Treg 的关键调节因子 我们将通过三个具体目标来检验这一假设，在目标 1 中，我们将确定。 为什么 Treg 特异性 Tim-3 KO 小鼠的肿瘤中 eTreg 较少？在目标 2 中，我们将定义其影响。 最后，在目标 3 中，我们将确定 Tim-3 的丢失如何影响肿瘤微环境。 在两种小鼠模型中，Treg 都会影响对 PD-1 检查点封锁的反应，并扩展到 头颈癌患者对 PD-1 阻断疗法的反应中相互作用的作用。 总之，这些研究将为更合理地将 Tim-3 转化为治疗靶点提供基础 在现有的检查点靶点（如 PD-1）的背景下，这些研究代表了实体瘤的逻辑。 延长本资助项目上一个周期中开展的工作。

项目成果

Immune regulation by Tim-3 [version 1; peer review: 2 approved]

Tim-3 的免疫调节 [版本 1；

• 发表时间: 2024-09-13
• 作者: Hridesh Banerjee;L. Kane;M. Ostrowski;Mei
• 通讯作者: Mei