A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities
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.
Authors
- Giuseppina Astone (ORCID: https://orcid.org/0000-0003-4206-3491)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Inna Khodos
- Giorgio Inghirami (ORCID: https://orcid.org/0000-0001-5566-0864)
- Brunangelo Falini (ORCID: https://orcid.org/0000-0002-7198-5965)
- Domenico Novero
- Robin Foà (ORCID: https://orcid.org/0000-0002-5021-3026)
- Zhaoqi Liu (ORCID: https://orcid.org/0000-0002-3798-9583)
- Roberto Piva (ORCID: https://orcid.org/0000-0002-2273-3470)
- Ruchi P. Patel (ORCID: https://orcid.org/0000-0001-8366-1928)
- Anton Karelin
- Nicolás Di Siervi (ORCID: https://orcid.org/0000-0002-9035-8174)
- Danilo Fiore (ORCID: https://orcid.org/0000-0003-3004-6862)
- Wing C. Chan (ORCID: https://orcid.org/0000-0002-6243-6008)
- Lúcio Queiroz (ORCID: https://orcid.org/0000-0002-6090-1834)
- Paola Ghione (ORCID: https://orcid.org/0000-0001-6986-7954)
- Maurilio Ponzoni (ORCID: https://orcid.org/0000-0002-0055-325X)
- Joshua Brody (ORCID: https://orcid.org/0000-0002-0850-6730)
- Claudia Pignataro
- Ekaterina Postovalova (ORCID: https://orcid.org/0000-0002-3413-3122)
- Marcello Gaudiano
- David M. Weinstock (ORCID: https://orcid.org/0000-0002-8724-3907)
- Valentina Fragliasso (ORCID: https://orcid.org/0000-0002-4189-0316)
- Joo Y. Song (ORCID: https://orcid.org/0000-0003-3497-2513)
- Luca Vincenzo Cappelli (ORCID: https://orcid.org/0000-0001-8090-3880)
- Paul Zumbo (ORCID: https://orcid.org/0000-0001-7234-2024)
- Oliver Elemento
- Sanjay S. Patel (ORCID: https://orcid.org/0000-0001-7621-453X)
- Laura Santambrogio (ORCID: https://orcid.org/0000-0002-4674-7041)
- Francesca Zammarchi (ORCID: https://orcid.org/0000-0001-9457-2170)
- Peter Martin (ORCID: https://orcid.org/0000-0001-7813-1551)
- Anastasia Nikitina (ORCID: https://orcid.org/0000-0002-9458-3432)
- Andrew M. Intlekofer (ORCID: https://orcid.org/0000-0001-9046-6549)
- Maria Sorokina (ORCID: https://orcid.org/0000-0003-1541-9480)
- Sandrine Degryse
- Simone Gardini
- Alexander Bagaev (ORCID: https://orcid.org/0000-0002-8680-854X)
- Rodolfo Machiorlatti
- Fabrizio Tabbò (ORCID: https://orcid.org/0000-0001-8525-2992)
- Liron Yoffe (ORCID: https://orcid.org/0000-0002-3040-8205)
- Jia Ruan
- Maria Teresa Cacciapuoti (ORCID: https://orcid.org/0000-0002-4904-3453)
- Raúl Rabadán (ORCID: https://orcid.org/0000-0001-7946-9255)
- Enzo Médico (ORCID: https://orcid.org/0000-0002-3917-2438)
- Leandro Cerchietti (ORCID: https://orcid.org/0000-0003-0608-1350)
- Gabriele Macari (ORCID: https://orcid.org/0000-0001-7519-4418)
- A. Moskowitz
- Clarisse Kayembe
- Enrico Tiacci (ORCID: https://orcid.org/0000-0001-8055-0931)
- Wayne Tam (ORCID: https://orcid.org/0000-0003-4283-0005)
- Ekaterina E. Belova (ORCID: https://orcid.org/0000-0002-7779-3673)
- Francesco Bertoni (ORCID: https://orcid.org/0000-0001-5637-8983)
- Luciana Cafforio
- Dmitry Tychinin
- Giorgia Zanetti (ORCID: https://orcid.org/0000-0002-3194-0877)
- Jude M. Phillip (ORCID: https://orcid.org/0000-0002-2999-5254)
- Daniil Nikitin (ORCID: https://orcid.org/0000-0001-7293-0272)
- Steven M. Horwitz (ORCID: https://orcid.org/0000-0002-6399-2006)
- Doron Betel (ORCID: https://orcid.org/0000-0002-8006-7752)
- Nahuel Zamponi (ORCID: https://orcid.org/0000-0002-9596-1095)
- Zachary Epstein (ORCID: https://orcid.org/0000-0002-6650-1655)
- Claudio Zanettini (ORCID: https://orcid.org/0000-0001-5043-8033)
- Marco Ruella (ORCID: https://orcid.org/0000-0003-4301-5811)
- Jaspreet Osan (ORCID: https://orcid.org/0000-0001-7297-1912)
- Nikita Kotlov (ORCID: https://orcid.org/0000-0002-6393-7357)
- Viktor Svekolkin (ORCID: https://orcid.org/0000-0001-5763-7246)
- Katerina Tikhonova
- Anqi Wang (ORCID: https://orcid.org/0009-0000-5321-8917)
- Xueshuai Han
- Chengqi Xu (ORCID: https://orcid.org/0000-0003-3361-8117)
- Olga Kudryashova (ORCID: https://orcid.org/0000-0003-3320-7764)
- Samuel Y. Ng
- Abigail Taylor
- William C. Chiu (ORCID: https://orcid.org/0000-0002-3806-6844)
- Giovanni Medico
- Ruiz Arvin Eric
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- City Of Hope National Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- NewYork–Presbyterian Hospital (US)
- Cornell University (US)
- University of Perugia (IT)
- Hospital of the University of Pennsylvania (US)
- Beijing Institute of Genomics (CN)
- San Raffaele University of Rome (IT)
- Lander Institute (IL)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Azienda Ospedaliera di Perugia (IT)
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- Presbyterian Hospital (US)
- Institute of Oncology Research (CH)
- Addgene (US)
- Department of Medical Sciences (RU)
- Adc Therapeutics (Switzerland) (CH)
- Ospedale Santa Maria (IT)
- Dana-Farber Cancer Institute (US)
- Boston Engineering (United States) (US)
- Lymphoma Research Foundation (US)
- Torino e-district (IT)
- Institute for Experimental Endocrinology and Oncology (IT)
- Azienda Sanitaria Locale CN2 (IT)
- Candiolo Cancer Institute (IT)
- Center for Genomic Science (IT)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Weill Cornell Medicine (US)
- University of Turin (IT)
- University of Naples Federico II (IT)
- Columbia University (US)
- University of Pennsylvania (US)
- Sapienza University of Rome (IT)
- Repligen (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102029
- Citations
- 7
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 7.32
Funders
- Leukemia and Lymphoma Society
- American-Italian Cancer Foundation
- National Natural Science Foundation of China
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Stand Up To Cancer