Defining the Role of CD26 in Checkpoint Blockaded Induced Tumor Immunity

定义 CD26 在检查点阻断诱导肿瘤免疫中的作用

• 批准号: 10621564
• 负责人: Chrystal Mary Paulos
• 金额: $ 8.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-13 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621564
• 关键词: Defining; Role; CD26; Checkpoint; Blockaded

Abstract: The objective of this MPI R21 is to support an important discovery found by this basic T cell immunologist and immune-therapist (Dr. Chrystal Paulos) and surgeon and scientist (Dr. David Neskey) research team in a Phase II clinical trial (NCT03021993) in patients with oral cavity squamous cell carcinoma (OCC). These patients were treated with Nivolumab as a novel neoadjuvant pre-surgical therapy at our institution (Hollings Cancer Center). Our unpublished work reveals that a remarkable 44% of patients responded to this therapy via pathological score. While promising, 56% of the patients remain unresponsive to this treatment. Our new data reveals that responders express higher CD26 (co-stimulatory molecule with enzyme activity) on tumor- infiltrating lymphocytes (TILs), while CD26 was far lower on TILs from non-responders. These data suggest that CD26 plays a critical role in the function and migration of antitumor T cells to the oppressive tumor microenvironment in patients responsive to PD-1 therapy. We propose to gain insight into CD26-expressing T cells in the tumor, positing that the enzymatic CD26 activity augments the function, migration and antitumor activity of human TILs (Aim 1) and that targeting this pathway can improve cancer immunotherapy in non- responders: an idea we will explore in Aim 2, using our highly clinically relevant OCC tumor models. Overall, the proposed research is expected to demonstrate that manipulation of the CD26 pathway may sufficiently induce durable immunity against advanced OCC tumors and rescue patients non-responsive to PD-1 therapy.

抽象的： 该MPI R21的目的是支持该基本T细胞免疫学家和 免疫治疗师（Chrystal Paulos博士）和外科医生兼科学家（David Neskey博士）研究团队 II期临床试验（NCT03021993）对口腔鳞状细胞癌患者（OCC）。这些 患者在我们机构中用Nivolumab作为一种新型的新辅助治疗（Hollings）治疗 癌症中心）。我们未发表的工作表明，有44％的患者通过 病理评分。有希望的虽然有56％的患者对这种治疗无反应。我们的新数据 表明响应者对肿瘤表达较高的CD26（与酶活性的共刺激分子） 浸润性淋巴细胞（TILS），而CD26在非反应者的TIL上要低得多。这些数据暗示 该CD26在抗肿瘤T细胞向压迫性肿瘤的功能和迁移中起关键作用 对PD-1治疗有反应的患者的微环境。我们建议深入了解表达CD26的T 肿瘤中的细胞，认为酶CD26活性增强了功能，迁移和抗肿瘤 人类tils的活性（AIM 1）和针对该途径可以改善非癌症的免疫疗法 响应者：我们将使用高度临床相关的OCC肿瘤模型在AIM 2中探索这个想法。全面的， 预计拟议的研究将证明对CD26途径的操纵可能足够 诱导对先进OCC肿瘤的持久免疫力，并挽救对PD-1治疗无反应的患者。