一个患者来源的T细胞淋巴瘤生物样本库揭示了致病机制和宿主相关的治疗弱点。

A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities.

作者信息

Fiore Danilo, Cappelli Luca Vincenzo, Zhaoqi Liu, Kotlov Nikita, Sorokina Maria, Phillip Jude, Zumbo Paul, Yoffe Liron, Ghione Paola, Wang Anqi, Han Xueshuai, Taylor Abigail, Chiu William, Fragliasso Valentina, Tabbo Fabrizio, Zamponi Nahuel, Di Siervi Nicolás, Kayembe Clarisse, Medico Giovanni, Patel Ruchi P, Gaudiano Marcello, Machiorlatti Rodolfo, Astone Giuseppina, Cacciapuoti Maria Teresa, Zanetti Giorgia, Pignataro Claudia, Eric Ruiz Arvin, Patel Sanjay, Zammarchi Francesca, Zanettini Claudio, Queiroz Lucio, Nikitina Anastasia, Kudryashova Olga, Karelin Anton, Nikitin Daniil, Tychinin Dmitry, Postovalova Ekaterina, Bagaev Alexander, Svekolkin Viktor, Belova Ekaterina, Tikhonova Katerina, Degryse Sandrine, Xu Chengqi, Novero Domenico, Ponzoni Maurilio, Tiacci Enrico, Falini Brunangelo, Song Joo, Khodos Inna, De Stanchina Elisa, Macari Gabriele, Cafforio Luciana, Gardini Simone, Piva Roberto, Medico Enzo, Ng Samuel Y, Moskowitz Allison, Epstein Zachary, Intlekofer Andrew, Ahmed Dogan, Chan Wing C, Martin Peter, Ruan Jia, Bertoni Francesco, Foà Robin, Brody Joshua D, Weinstock David M, Osan Jaspreet, Santambrogio Laura, Elemento Oliver, Betel Doron, Tam Wayne, Ruella Marco, Cerchietti Leandro, Rabadan Raul, Horwitz Steven, Inghirami Giorgio

机构信息

Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; Institute for Experimental Endocrinology and Oncology, "G.Salvatore" IEOS, Consiglio Nazionale delle Ricerche (CNR), 80131 Naples, Italy.

Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

出版信息

Cell Rep Med. 2025 Apr 15;6(4):102029. doi: 10.1016/j.xcrm.2025.102029. Epub 2025 Mar 26.

DOI:10.1016/j.xcrm.2025.102029

PMID:40147445

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12047492/

Abstract

Peripheral T cell lymphomas (PTCLs) comprise heterogeneous malignancies with limited therapeutic options. To uncover targetable vulnerabilities, we generate a collection of PTCL patient-derived tumor xenografts (PDXs) retaining histomorphology and molecular donor-tumor features over serial xenografting. PDX demonstrates remarkable heterogeneity, complex intratumor architecture, and stepwise trajectories mimicking primary evolutions. Combining functional transcriptional stratification and multiparametric imaging, we identify four distinct PTCL microenvironment subtypes with prognostic value. Mechanistically, we discover a subset of PTCLs expressing Epstein-Barr virus-specific T cell receptors and uncover the capacity of cancer-associated fibroblasts of counteracting treatments. PDXs' pre-clinical testing captures individual vulnerabilities, mirrors donor patients' clinical responses, and defines effective patient-tailored treatments. Ultimately, we assess the efficacy of CD5KO- and CD30- Chimeric Antigen Receptor T Cells (CD5KO-CART and CD30_CART, respectively), demonstrating their therapeutic potential and the synergistic role of immune checkpoint inhibitors for PTCL treatment. This repository represents a resource for discovering and validating intrinsic and extrinsic factors and improving the selection of drugs/combinations and immune-based therapies.

摘要

外周T细胞淋巴瘤（PTCL）是一类异质性恶性肿瘤，治疗选择有限。为了发现可靶向的脆弱性，我们构建了一组源自PTCL患者的肿瘤异种移植模型（PDX），这些模型在连续异种移植过程中保留了组织形态学和分子供体肿瘤特征。PDX显示出显著的异质性、复杂的肿瘤内结构以及模拟原发肿瘤演变的逐步轨迹。结合功能转录分层和多参数成像，我们确定了四种具有预后价值的不同PTCL微环境亚型。机制上，我们发现了一部分表达爱泼斯坦-巴尔病毒特异性T细胞受体的PTCL，并揭示了癌症相关成纤维细胞对抗治疗的能力。PDX的临床前测试捕捉到个体脆弱性，反映供体患者的临床反应，并确定有效的个体化治疗方案。最终，我们评估了CD5敲除和CD30嵌合抗原受体T细胞（分别为CD5KO-CART和CD30_CART）的疗效，证明了它们的治疗潜力以及免疫检查点抑制剂在PTCL治疗中的协同作用。这个资源库是发现和验证内在和外在因素、改善药物/联合治疗及基于免疫治疗选择的一个资源。