Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer

通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制

• 批准号: 9447149
• 负责人: Linda Mac Pherson Bradley
• 金额: $ 21.21万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447149
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Antitumor Response; Antiviral Agents; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Adhesion Molecules; Cell Survival; Cells; Chronic; Clinical; Coupled; Cytotoxic T-Lymphocyte-Associated Protein 4; Dendritic Cells; Down-Regulation; Engineering; Extracellular Matrix; Family; Functional disorder; Genetic; Goals; Hematopoietic; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunosuppression; Immunotherapy; Interleukin-2; Ligands; Ligation; Malignant Neoplasms; Mediating; Memory; Metastatic Melanoma; Modeling; Mus; Outcome; P-selectin ligand protein; Pathway interactions; Patients; Phenotype; Process; Receptor Signaling; SILV gene; SLEB2 gene; Selectins; Signal Transduction; T cell regulation; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Tumor Immunity; Virus Diseases; adhesion receptor; base; cancer immunotherapy; cancer therapy; cell motility; chemokine; exhaust; exhaustion; fundamental research; immune checkpoint blockade; improved; inhibitor/antagonist; insight; macrophage; melanoma; mouse model; neoplastic cell; novel; optimism; patient subsets; preservation; prevent; receptor; response; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY New advances in immunotherapy for cancer, based on decades of fundamental research on the regulation of T cells, have yielded tremendous optimism that even aggressive and fatal cancers, including metastatic melanoma, can one day be cured in the vast majority of patients. However, current approaches benefit only a subset of patients, and new insights into immune processes are urgently needed to define the means to improve therapies and achieve clinical benefits for a variety of different cancers. We recently discovered that the adhesion receptor, PSGL-1 (P-selectin glycoprotein ligand-1), is a new checkpoint inhibitor of T responses to chronic viral infection and a potent regulator of anti-tumor responses. The goal of this project is to determine if targeting PSGL-1 (Selplg) in tumor-specific CD8+ and/or CD4+ T cells represents a strategy to mitigate tolerance of melanoma tumors when used for adoptive cell therapy alone and when combined with additional approaches to alleviate immune suppression. Our studies showed that genetic deletion of PSGL-1 led to downregulation of multiple inhibitory receptors that are hallmarks of dysfunctional or “exhausted” T cells including PD-1, LAG3, CD160, BTLA and TIM3, indicating that PSGL-1 modulates expression of other checkpoint inhibitors. PSGL-1-deficiency did not alter T cell migration into tissues, but rather enabled CD8+ and CD4+ T cells to mount much greater effector responses due to enhanced survival of multifunctional T cells that mediated effective anti-viral and anti-tumor responses. Our results demonstrate that this receptor may be a novel target with the potential to reverse immune suppression in patients whose cancers are unresponsive or have suboptimal responses to other immunotherapies. In mice, PSGL-1- deficiency led to dramatic control of melanoma tumor growth that was coupled with greater numbers of tumor infiltrating, multifunctional CD8+ and CD4+ T cells that expressed lower levels of PD-1. However, when tumor- specific CD8+ T cells were used to treat tumor-bearing mice by adoptive transfer, tumor control was not sustained, indicating loss of T cell anti-tumor response. In this application, we will test the hypothesis that genetic deletion of PSGL-1 in tumor-specific CD4+ and CD8+ T cells used for adoptive cell therapy, particulalry in combination, can dramatically enhance anti-tumor responses (Aim 1), but their functionality and preservation can be optimized when other mechanisms underlying T cell exhaustion are concurrently inhibited (Aim 2). We will also address whether TCR “engineered” T cells can form memory and whether checkpoint blockade is advantageous or deleterious for memory T cell induction.

项目摘要 癌症免疫治疗的新进展，基于数十年来对T细胞调节的基础研究。 细胞，已经取得了巨大的乐观，即使是侵略性和致命的癌症，包括转移性 黑色素瘤，有一天绝大多数患者都可以治愈。然而，目前的方法仅有利于 患者的子集，以及对免疫过程的新见解，迫切需要定义 改善治疗方法，并为各种不同的癌症带来临床益处。我们最近发现 粘附受体PSGL-1（P-selectin glycoprotein ligand-1）是一种新T细胞检查点抑制剂 对慢性病毒感染的反应和抗肿瘤反应的有效调节剂。这个目标 项目是确定在肿瘤特异性CD 8+和/或CD 4 + T细胞中靶向PSGL-1（Selplg）是否代表了肿瘤特异性免疫应答。 当单独用于过继细胞疗法时和当单独用于过继细胞疗法时减轻黑素瘤肿瘤耐受性的策略 结合其他方法来减轻免疫抑制。我们的研究表明， PSGL-1的缺失导致多种抑制性受体的下调，这些受体是功能障碍或 包括PD-1、LAG 3、CD 160、BTLA和TIM 3的“耗尽的”T细胞，表明PSGL-1调节了T细胞的增殖。 其他检查点抑制剂的表达。PSGL-1缺乏并不改变T细胞向组织中的迁移， 而使CD 8+和CD 4 + T细胞能够产生更大的效应子应答，这是由于增强了T细胞的存活率。 多功能T细胞介导有效的抗病毒和抗肿瘤反应。我们的结果证实 这种受体可能是一种新的靶点，具有逆转患者免疫抑制的潜力， 癌症对其他免疫疗法无反应或具有次优反应。在小鼠中，PSGL-1- 缺乏导致了黑色素瘤肿瘤生长的显着控制，这与更多的肿瘤 浸润性多功能CD 8+和CD 4 + T细胞表达较低水平的PD-1。然而，当肿瘤- 特异性CD 8 + T细胞被用于通过过继转移治疗荷瘤小鼠，肿瘤控制不被 持续，表明T细胞抗肿瘤应答的丧失。在本申请中，我们将检验以下假设： 用于过继性细胞治疗的肿瘤特异性CD 4+和CD 8 + T细胞中PSGL-1的遗传缺失， 特别是联合使用，可以显著增强抗肿瘤反应（目的1），但它们的 当T细胞耗竭的其他潜在机制时， 同时受到抑制（目标2）。我们还将讨论TCR“工程化”T细胞是否可以形成记忆 以及检查点阻断对记忆T细胞诱导是有利还是有害。