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 Our unpublished work reveals that a remarkable 44% of patients responded to this therapy via pathological score.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： MPI R21 的目的是支持这位基础 T 细胞免疫学家发现的重要发现 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 针对口腔鳞状细胞癌 (OCC) 患者的 II 期临床试验 (NCT03021993)。这些 在我们的机构中​​，患者接受了纳武单抗作为一种新型新辅助术前治疗（Hollings 癌症中心）。我们未发表的研究表明，44% 的患者通过以下方式对这种疗法做出了反应： 病理评分。虽然这种治疗很有希望，但 56% 的患者仍然没有反应。我们的新数据 揭示了反应者在肿瘤上表达更高的 CD26（具有酶活性的共刺激分子） 浸润淋巴细胞（TIL），而无反应者的 TIL 上的 CD26 则要低得多。这些数据表明 CD26 在抗肿瘤 T 细胞的功能和向压迫性肿瘤的迁移中发挥着关键作用 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 肿瘤细胞，推测 CD26 酶活性增强功能、迁移和抗肿瘤 人类 TIL 的活性（目标 1），并且靶向该途径可以改善非癌症患者的癌症免疫治疗 反应者：我们将在目标 2 中使用我们高度临床相关的 OCC 肿瘤模型来探索这一想法。全面的， 拟议的研究预计将证明 CD26 通路的操纵可能足以 诱导针对晚期 OCC 肿瘤的持久免疫力，并拯救对 PD-1 治疗无反应的患者。