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

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-03-24 DOI:10.1016/j.xcrm.2025.102029

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

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引用次数: 0

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.

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.