Targeting oncogenic TCR signaling in PTCL

项目摘要 CD 25以前被鉴定为异源三聚体IL 2受体（IL 2 R）的α链。的高表达水平 CD 25以前归因于T细胞活化或调节性T细胞中Foxp 3的转录活化 （Tennis）.我们的初步实验表明，CD 25不仅是IL 2 R链，而且实际上结合CD 3 T细胞受体（TCR）的信号链，用于反馈控制TCR信号强度。 反映其在正常T细胞发育中的中心作用，TCR及其下游信号传导途径是一种免疫调节剂。 在大多数外周T细胞淋巴瘤（PTCL）的致癌转化的目标。致癌 TCR模拟物即使在不存在功能性TCR的情况下也促进存活和增殖。致癌TCR模拟物 包括TCR信号传导链CD 3 β、近端酪氨酸激酶（PTK; FYN、LCK、ZAP 70）的活化损伤 和ITK-SYK、NPM 1-ALK融合物。与此P01的其他研究人员合作，我们的团队最近 发现淋巴恶性肿瘤独特地依赖于PTK的反馈调节（Chen等， Nature 2015）、PI 3 K（Shojaee等人，Nature Med 2016; Chan等人，Nature 2017）和ERK（Shojaee等人，癌 Cell 2015; Xiao等人，Cell 2018）。在此，我们证实了在多种PTCL亚型中，CD 25 协调所有三种途径（PTKs、PI 3 K和ERK）的反馈控制。 该项目的中心目标是提供一个全面的战略，以针对CD 25介导的反馈 控制致癌TCR信号传导以克服难治性PTCL的耐药性。以下三 目的：（1）阐明CD 25介导的TCR信号反馈调控PTCL的机制 亚型，（2）提供了将PI 3 K抑制剂与CD 25抗体-药物缀合物（ADC）组合的基本原理， (3)评估新开发的在T细胞和NK细胞中工程化的CD 25嵌合抗原受体（汽车）的功效 以及它们对内源性抗肿瘤免疫应答的影响。 目的1：PTCL中CD 25介导的致癌TCR信号反馈控制机制。 目的2：CD 25内吞和内体再循环作为致癌TCR信号转导的动态反馈控制 目的3：CD 25 CAR-T和CAR-NK细胞的临床前开发和验证。

PROJECT SUMMARY CD25 was previously identified as α-chain of the heterotrimeric IL2 receptor (IL2R). High expression levels of CD25 was previously attributed to T-cell activation or transcriptional activation by Foxp3 in regulatory T-cells (Tregs). Our preliminary experiments revealed that CD25 is not only an IL2R chain, but in fact binds the CD3 signal chains of the T-cell receptor (TCR) for feedback control of TCR signaling strength. Reflecting its central role in normal T-cell development, the TCR and its downstream signaling pathway is a target of oncogenic transformation in the majority of peripheral T-cell lymphomas (PTCLs). Oncogenic TCR-mimics promote survival and proliferation even in the absence of a functional TCR. Oncogenic TCR-mimics include activating lesions of the TCR-signaling chain CD3ζ, proximal tyrosine kinases (PTKs; FYN, LCK, ZAP70) and ITK-SYK, NPM1-ALK fusions. In collaboration with other investigators of this P01, our group recently discovered that lymphoid malignancies are uniquely dependent on feedback regulation of PTKs (Chen et al., Nature 2015), PI3K (Shojaee et al., Nature Med 2016; Chan et al., Nature 2017) and ERK (Shojaee et al., Cancer Cell 2015; Xiao et al., Cell 2018). Here we validate the concept that in multiple PTCL subtypes, CD25 orchestrates feedback control of all three pathways (PTKs, PI3K and ERK). The central goal of this project is to deliver a comprehensive strategy to target CD25-mediated feedback control of oncogenic TCR signaling to overcome drug resistance in refractory PTCL. The following three Aims will (1) elucidate the mechanism of CD25-mediated feedback control of oncogenic TCR-signaling in PTCL subtypes, (2) provide a rationale for combining PI3K inhibitors with CD25 antibody-drug conjugates (ADC) and (3) evaluate efficacy of newly developed CD25 chimeric antigen receptors (CARs) engineered in T- and NK-cells and their effects on endogenous anti-tumor immune responses. Aim 1: Mechanisms of CD25-mediated feedback control of oncogenic TCR-signaling in PTCL. Aim 2: CD25-endocytosis and endosomal recycling as dynamic feedback control of oncogenic TCR-signaling Aim 3: Preclinical development and validation of CD25 CAR-T and CAR-NK cells.