Targeting oncogenic TCR signaling in PTCL

项目总结 CD25是异源三聚体白介素2受体(IL2R)的α链。高水平的表达 CD25以前被认为是由于调节性T细胞中的T细胞被Foxp3激活或转录激活 (Tregs)。我们的初步实验表明，CD25不仅是IL2R链，而且实际上与CD3结合 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细胞发育中的核心作用，TCR及其下游信号通路是一种 大多数外周T细胞淋巴瘤(PTCL)的致癌转化靶点。致癌作用 即使在没有功能TCR的情况下，TCR模拟物也能促进存活和增殖。致癌TCR-模拟物 包括激活TcR信号链CD3ζ、近端酪氨酸激酶(PTKs；FYN、LCK、ZAP70)的损伤 ITK-SYK、NPM1-ALK融合。在与本P01的其他调查人员合作下，我们小组最近 发现淋巴系统恶性肿瘤唯一依赖于PTKs的反馈调节(Chen等人， 自然2015)、PI3K(Shojaee等人，《自然医学》2016；Chan等人，《自然》2017)和ERK(Shojaee等人，癌症 Cell 2015；肖等人，Cell 2018)。在这里，我们验证了在多个PTCL亚型中，CD25 协调所有三个通路(PTK、PI3K和ERK)的反馈控制。 该项目的中心目标是提供针对CD25中介反馈的全面策略 控制致癌TCR信号以克服难治性PTCL的耐药性。以下三项 AIMS将(1)阐明CD25对PTCL中致癌TCR信号的反馈调控机制 亚型，(2)提供了将PI3K抑制剂与CD25抗体-药物结合物(ADC)相结合的理论基础，以及 (3)评价T细胞和NK细胞中新开发的CD25嵌合抗原受体(CARS)的疗效 以及它们对内源性抗肿瘤免疫反应的影响。 目的1：CD25对PTCL中致癌TCR信号的反馈调控机制。 目的2：CD25内吞和内体循环作为致癌TCR信号的动态反馈控制 目的3：CD25 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.