Defining the Role of CD26 in Checkpoint Blockaded Induced Tumor Immunity

摘要： 这个MPI R21的目的是支持这个基础T细胞免疫学家发现的一个重要发现， 免疫治疗师（Chrystal Paulos博士）和外科医生兼科学家（大卫Neskey博士）研究小组在一个 口腔鳞状细胞癌（OCC）患者的II期临床试验（NCT 03021993）。这些 在我们的机构（Hollings），患者接受纳武单抗作为一种新型的新辅助术前治疗 癌症中心）。我们未发表的研究表明，44%的患者对这种疗法有反应， 病理评分虽然前景看好，但56%的患者对这种治疗仍然没有反应。我们的新数据 揭示了应答者在肿瘤上表达更高的CD26（具有酶活性的共刺激分子）， 在浸润性淋巴细胞（TIL）上，CD26显著降低，而在来自非应答者的TIL上，CD26显著降低。这些数据表明 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细胞， 细胞在肿瘤中，假定酶CD26活性增强功能，迁移和抗肿瘤 人TIL的活性（Aim 1），靶向该途径可以改善非肿瘤患者的癌症免疫治疗。 反应者：我们将在目标2中探索这一想法，使用我们高度临床相关的OCC肿瘤模型。总体而言， 这项拟议中的研究有望证明，操纵CD26通路可能足以 诱导针对晚期OCC肿瘤的持久免疫力并拯救对PD-1治疗无应答的患者。

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 Our unpublished work reveals that a remarkable 44% of patients responded to this therapy via pathological score.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.