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

   

Authors:	Fiore, D.; Cappelli, L. V.; Zhaoqi, L.; Kotlov, N.; Sorokina, M.; Phillip, J.; Zumbo, P.; Yoffe, L.; Ghione, P.; Wang, A.; Han, X.; Taylor, A.; Chiu, W.; Fragliasso, V.; Tabbo, F.; Zamponi, N.; Di Siervi, N.; Kayembe, C.; Medico, G.; Patel, R. P.; Gaudiano, M.; Machiorlatti, R.; Astone, G.; Cacciapuoti, M. T.; Zanetti, G.; Pignataro, C.; Eric, R. A.; Patel, S.; Zammarchi, F.; Zanettini, C.; Queiroz, L.; Nikitina, A.; Kudryashova, O.; Karelin, A.; Nikitin, D.; Tychinin, D.; Postovalova, E.; Bagaev, A.; Svekolkin, V.; Belova, E.; Tikhonova, K.; Degryse, S.; Xu, C.; Novero, D.; Ponzoni, M.; Tiacci, E.; Falini, B.; Song, J.; Khodos, I.; De Stanchina, E.; Macari, G.; Cafforio, L.; Gardini, S.; Piva, R.; Medico, E.; Ng, S. Y.; Moskowitz, A.; Epstein, Z.; Intlekofer, A.; Ahmed, D.; Chan, W. C.; Martin, P.; Ruan, J.; Bertoni, F.; Foà, R.; Brody, J. D.; Weinstock, D. M.; Osan, J.; Santambrogio, L.; Elemento, O.; Betel, D.; Tam, W.; Ruella, M.; Cerchietti, L.; Rabadan, R.; Horwitz, S.; Inghirami, G.
Article Title:	A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities
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. © 2025 The Authors
Keywords:	immunohistochemistry; controlled study; human tissue; gene mutation; human cell; histopathology; nonhuman; flow cytometry; binding affinity; mouse; animal tissue; bortezomib; gene expression; animal experiment; animal model; cyclophosphamide; morphology; peripheral t cell lymphoma; t cell lymphoma; xenograft; real time polymerase chain reaction; microenvironment; dna extraction; epstein barr virus; azacitidine; peripheral blood mononuclear cell; electrophoresis; rna extraction; belinostat; stratification; tumor microenvironment; copy number variation; histomorphology; phylogenetic tree; navitoclax; clonal evolution; crizotinib; pi3k/akt signaling; immune checkpoint inhibitor; high throughput sequencing; brentuximab vedotin; human; article; precision medicine; ceritinib; immunofluorescence assay; differential expression analysis; luminespib; venetoclax; car-t; whole exome sequencing; crenolanib; biobank; kegg; single cell rna seq; cerdulatinib; tucidinostat; machine learning algorithm; drug screenings; patient-derived tumor xenografts; pre-clinical trials; repository; iberdomide; mac-1 cell line; ms-5 cell line; sup-m2 cell line
Journal Title:	Cell Reports Medicine
Volume:	6
Issue:	4
ISSN:	2666-3791
Publisher:	Cell Press
Date Published:	2025-04-15
Start Page:	102029
Language:	English
DOI:	10.1016/j.xcrm.2025.102029
PUBMED:	40147445
PROVIDER:	scopus
PMCID:	PMC12047492
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105001129663&doi=10.1016%2fj.xcrm.2025.102029&partnerID=40&md5=691a2e4dcb7fc7d078e695b4b1bcbd48
Notes:	Article -- MSK author Ahmet Dogan's name is misspelled as 'Dogan Ahmed' on the original publication -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/224602