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: 9250721
• 负责人: Robert L. Ferris
• 金额: $ 49.56万
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250721
• 关键词: Adaptive Immune System; Affect; Antibodies; Biochemical; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cells; Cessation of life; Clinical; Clinical Data; Data; Event; FDA approved; FRAP1 gene; Functional disorder; Genetic Recombination; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Impairment; In Situ; Lead; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Mono-S; Mus; Pathway interactions; Patients; Physiological; Process; Proteins; Publishing; Receptor Activation; Receptor Signaling; Resistance; Signal Pathway; Signal Transduction; Solid Neoplasm; Staining method; Stains; System; T Cell Receptor Signaling Pathway; T cell regulation; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Tissues; Transgenic Organisms; Tumor-Infiltrating Lymphocytes; Up-Regulation; Work; base; cancer cell; cancer immunotherapy; cancer therapy; cell type; clinical efficacy; combinatorial; exhaust; exhaustion; experience; head and neck cancer patient; interest; mTOR Signaling Pathway; mouse model; novel; objective response rate; outcome forecast; patient subsets; pre-clinical; public health relevance; receptor; response; success; targeted cancer therapy; therapy resistant; tool; tumor; tumor growth; tumor microenvironment

 DESCRIPTION (provided by applicant): The emerging field of "checkpoint" receptors has revealed a latent, and powerful, ability of the adaptive immune system to shrink or eliminate tumors. Single agent response rates for checkpoint inhibitors, such as anti-PD-1 are still relatively low and preliminary results suggest that combinatorial approaches are significantly more effective. Recent studies have demonstrated that co-expression of PD-1 and the emerging checkpoint molecule Tim-3 is frequent in tumor infiltrating lymphocytes (TIL) and pre-clinical data suggest that combined targeting of PD-1 and Tim-3 produces synergistic effects on tumor regression. However, it is not clear how antibodies targeting these proteins, either in mono- or duo-therapy, modulate downstream signaling events. Resistance (or therapeutic escape) could also occur due to "compensatory" upregulation of an alternative checkpoint receptor after blockade of a single receptor, mediated in part by intracellular signaling "cross talk." Molecular or functional cooperation between these proteins has not been examined in the context of freshly isolated TIL from human cancer patients. Intriguingly, the PI3K/Akt/mTOR signaling pathway is known to be inhibited or activated by PD-1 or Tim-3, respectively, suggesting that this signaling pathway is an important node for the regulation of T cell exhaustion. Based on emerging data, we hypothesize that PD-1 and Tim-3 cooperate to control the function of tumor-infiltrating exhausted/effector CD8+ T cells, and that modulation of PD-1 and Tim-3 signaling cross-talk modulates T cell receptor (TCR) activation in cancer. We propose to define pathways of Tim-3/PD-1 signaling and functional crosstalk in tumor-infiltrating activated vs exhausted CD8+ CTL from head and neck cancer (HNC) patients. We will then determine the extent to which Tim-3 modifies the effects of PD-1 on activated effector vs. exhausted CTL in a mouse model of HNC. Lastly, we will define pathways of compensatory ICR expression and function in response to PD-1 or Tim-3 blockade.

 描述（由申请人提供）：“检查点”受体的新兴领域揭示了适应性免疫系统缩小或消除肿瘤的潜在且强大的能力，例如抗PD-1抑制剂的单药反应率。仍然相对较低，初步结果表明组合方法明显更有效，最近的研究表明 PD-1 和新兴检查点分子 Tim-3 的共表达在肿瘤浸润淋巴细胞 (TIL) 和临床前数据表明，PD-1 和 Tim-3 的联合靶向对肿瘤消退产生协同作用，但目前尚不清楚靶向这些蛋白的抗体（无论是单药治疗还是双药治疗）如何调节下游信号转导事件。 （或治疗逃逸）也可能是由于阻断单个受体后替代检查点受体的“补偿性”上调而发生，部分由细胞内信号“串扰”介导。这些蛋白质之间的分子或功能合作尚未得到研究。语境有趣的是，已知 PI3K/Akt/mTOR 信号通路分别被 PD-1 或​​ Tim-3 抑制或激活，这表明该信号通路是调节 TIL 的重要节点。 T 细胞耗竭。基于新出现的数据，我们研究了 PD-1 和 Tim-3 协同控制肿瘤浸润耗竭/效应 CD8+ T 细胞的功能，以及 PD-1 和 Tim-3 信号传导的调节。串扰调节癌症中的 T 细胞受体 (TCR) 激活 我们建议定义头颈癌 (HNC) 患者肿瘤浸润性激活与耗尽 CD8+ CTL 中 Tim-3/PD-1 信号传导和功能串扰的通路。然后，我们将在 HNC 小鼠模型中确定 Tim-3 对激活的效应器与耗尽的 CTL 的影响程度，最后，我们将定义响应 PD-1 的补偿性 ICR 表达和功能的途径。或 Tim-3 封锁。