T-cell lymphomas (TCLs) comprise a heterogeneous group of malignancies. Current therapeutic options remain limited, partly given the scarcity of representative preclinical models. To uncover targetable vulnerabilities, we created a collection of TCL patient-derived-tumor-xenografts (PDXs) retaining molecular and histomorphology donor tumor features over serial xeno-grafting while capturing their mechanisms of lymphomagenesis and evolution. Ex-vivo cultures and in-vivo experiments demonstrated remarkable heterogeneity, complex intra-tumor genomic architecture, and stepwise genomic trajectories. The transcriptional representation of primary and PDXs led to a new classification comprising four novel microenvironment-based TCL subtypes. The library identified a unique subset expressing T-cell receptors recognizing Epstein-Barr Virus (EBV) peptides supporting a novel EBV-mediated tumorigenic mechanism. Mechanistically, we uncovered a pro-tumorigenic role of stromal elements and elucidated bidirectional lymphoma-microenvironment interactions. Importantly, PDXs captured individual vulnerabilities, mirrored donor patients' clinical responses, and defined effective patient-tailored treatments. This platform represents a public resource for discovering and validating oncogenic drivers and new drugs/combinations.
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Funding Information: G.I. is supported by CA229086, CA229100, CA195568, LLS 7011-16; L.V.C and R.F.: Italian Association for Cancer Research (AIRC, Milan, Italy), Metastases 5x1000 Special Program, grant 21198; L.V.C: American Italian Cancer Foundation (AICF) Post-Doctoral Research Fellowship; D.F: the Rita-Levi Montalcini grant from Italian Ministry of University and Research (MIUR). D.M.W. was supported by NCI R35 CA231958, NCI P01 CA233412, and Leukemia and Lymphoma Society Specialized Center of Research 7026-21. R.R., A.W. and Z.L. were supported by NCI R35 CA253126, U01CA243073 and Stand Up to Cancer Convergence Program. Z.L. was supported by the NSFC 32170565 and the CAS Hundred Talents Program. W.C.C. was supported by the COH Cancer Center Support Grant P30, CA033572 and 1PO1CA229100.
Declaration of Interests: D.M.W. is an employee of Merck and has equity interest in Ajax, Bantam and Travera. F.B.: institutional research funds from ADC Therapeutics, Bayer AG, Cellestia, Helsinn, HTG Molecular Diagnostics, ImmunoGen, iOnctura, Menarini Ricerche, NEOMED Therapeutics 1, Nordic Nanovector ASA, Sepxis AG; advisory board fees from Novarts; consultancy fee from Helsinn, Menarini; expert statements provided to HTG Molecular Diagnostics; travel grants from Amgen, Astra Zeneca, iOnctura.
Ethical Approval Statement: The collection of PTCL patient data and tissue for the generation and distribution of PDX and derivatives were performed according to the guidelines of the Institutional Review Board-Research at the Weill Cornell Medicine, Memorial Sloan Kettering's Institutional Review Board (IRB)/Privacy Board and the Comitato Etico Interaziendale, AOU San Giovanni Battista di Torino-A) CTO Maria Adelaide di Torino. All patients participating in the biobank study signed informed consent forms approved by the responsible authority.
Pathological samples were collected at the Weill Cornell Medicine (WCM) of New York, University of Torino, and Memorial Sloan Kettering Cancer Center (MSKCC). De-identified patients’ samples were obtained with informed consent under WCM, Torino, MSKCC, S. Raffaele at Milan, City of Hope, and Mount Sinai Institutional Review Boards (IRB)-approved protocols.
Mice were handled according WCM Institutional Animal Care and Use Committee (protocol #2014-24).
Fiore, Danilo and Cappelli, Luca Vincenzo and Zhaoqi, Liu and Kotlov, Nikita and Sorokina, Maria and Phillip, Jude and Zumbo, Paul and Yoffe, Liron and Ghione, Paola and Wang, Anqi and Han, Xueshuai and Chiu, William and Fragliasso, Valentina and Tabbò, Fabrizio and Zamponi, Nahuel and Kayembe, Clarisse and Gaudiano, Marcello and Machiorlatti, Rodolfo and Astone, Giuseppina and Cacciapuoti, Maria Teresa and Patel, Sanjay and Zammarchi, Francesca and Zanettini, Claudio and Queiroz, Lucio and Nikitina, Anastasia and Kudryashova, Olga and Karelin, Anton and Nikitin, Daniil and Tychinin, Dmitry and Postovalova, Ekaterina and Bagaev, Alexander and Svekolkin, Viktor and Belova, Ekaterina and Tikhonova, Katerina and Degryse, Sandrine and Novero, Domenico and Ponzoni, Maurilio and Tiacci, Enrico and Falini, Brunangelo and Song, Joo Y. and Khodos, Inna and De Stanchina, Elisa and Macari, Gabriele and Cafforio, Luciana and Gardini, Simone and Piva, Roberto and Medico, Enzo and NG, Samuel Y. and Moskowitz, Allison and Epstein, Zachary and Intlekofer, Andrew M. and Ahmed, Dogan and Martin, Peter and Ruan, Jia and Bertoni, Francesco and Foà, Robin and Brody, Joshua and Osan, Jaspreet and Santambrogio, Laura and Betel, Doron and Chan, John C. and Tam, Wayne and Weinstock, David M. and Cerchietti, Leandro and Rabadan, Raul and Horwitz, Steven and Inghirami, Giorgio G.A., A Patient-Derived T-Cell Lymphoma Biorepository Uncovers New Pathogenetic Mechanisms and Host-Related Therapeutic Vulnerabilities. Available at SSRN: https://ssrn.com/abstract=4529648 or http://dx.doi.org/10.2139/ssrn.4529648
This version of the paper has not been formally peer reviewed.
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