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

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

doi:10.1016/j.xcrm.2025.102029

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

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. PatelMarcello 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	102029
Journal	Cell Reports Medicine
DOIs	https://doi.org/10.1016/j.xcrm.2025.102029
State	Accepted/In press - 2025

Keywords

CAR-T
clonal evolution
drug screenings
microenvironment
patient-derived tumor xenografts
pre-clinical trials
precision medicine
repository
stratification
T cell lymphoma

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10.1016/j.xcrm.2025.102029

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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., ... Inghirami, G. (Accepted/In press). A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities. Cell Reports Medicine, Article 102029. https://doi.org/10.1016/j.xcrm.2025.102029

@article{18b2f0766d9a493587a7e80c3ac66c16,

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{\textquoteright} pre-clinical testing captures individual vulnerabilities, mirrors donor patients{\textquoteright} 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.",

keywords = "CAR-T, clonal evolution, drug screenings, microenvironment, patient-derived tumor xenografts, pre-clinical trials, precision medicine, repository, stratification, T cell lymphoma",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

doi = "10.1016/j.xcrm.2025.102029",

language = "English",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

}

Fiore, D, Cappelli, LV, 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, RP, Gaudiano, M, Machiorlatti, R, Astone, G, Cacciapuoti, MT, Zanetti, G, Pignataro, C, Eric, RA, 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, SY, Moskowitz, A, Epstein, Z, Intlekofer, A, Ahmed, D, Chan, WC, Martin, P, Ruan, J, Bertoni, F, Foà, R, Brody, JD, Weinstock, DM, Osan, J, Santambrogio, L, Elemento, O, Betel, D, Tam, W, Ruella, M, Cerchietti, L, Rabadan, R, Horwitz, S & Inghirami, G 2025, 'A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities', Cell Reports Medicine. https://doi.org/10.1016/j.xcrm.2025.102029

TY - JOUR

T1 - A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities

AU - Fiore, Danilo

AU - Cappelli, Luca Vincenzo

AU - Zhaoqi, Liu

AU - Kotlov, Nikita

AU - Sorokina, Maria

AU - Phillip, Jude

AU - Zumbo, Paul

AU - Yoffe, Liron

AU - Ghione, Paola

AU - Wang, Anqi

AU - Han, Xueshuai

AU - Taylor, Abigail

AU - Chiu, William

AU - Fragliasso, Valentina

AU - Tabbo, Fabrizio

AU - Zamponi, Nahuel

AU - Di Siervi, Nicolás

AU - Kayembe, Clarisse

AU - Medico, Giovanni

AU - Patel, Ruchi P.

AU - Gaudiano, Marcello

AU - Machiorlatti, Rodolfo

AU - Astone, Giuseppina

AU - Cacciapuoti, Maria Teresa

AU - Zanetti, Giorgia

AU - Pignataro, Claudia

AU - Eric, Ruiz Arvin

AU - Patel, Sanjay

AU - Zammarchi, Francesca

AU - Zanettini, Claudio

AU - Queiroz, Lucio

AU - Nikitina, Anastasia

AU - Kudryashova, Olga

AU - Karelin, Anton

AU - Nikitin, Daniil

AU - Tychinin, Dmitry

AU - Postovalova, Ekaterina

AU - Bagaev, Alexander

AU - Svekolkin, Viktor

AU - Belova, Ekaterina

AU - Tikhonova, Katerina

AU - Degryse, Sandrine

AU - Xu, Chengqi

AU - Novero, Domenico

AU - Ponzoni, Maurilio

AU - Tiacci, Enrico

AU - Falini, Brunangelo

AU - Song, Joo

AU - Khodos, Inna

AU - De Stanchina, Elisa

AU - Macari, Gabriele

AU - Cafforio, Luciana

AU - Gardini, Simone

AU - Piva, Roberto

AU - Medico, Enzo

AU - Ng, Samuel Y.

AU - Moskowitz, Allison

AU - Epstein, Zachary

AU - Intlekofer, Andrew

AU - Ahmed, Dogan

AU - Chan, Wing C.

AU - Martin, Peter

AU - Ruan, Jia

AU - Bertoni, Francesco

AU - Foà, Robin

AU - Brody, Joshua D.

AU - Weinstock, David M.

AU - Osan, Jaspreet

AU - Santambrogio, Laura

AU - Elemento, Oliver

AU - Betel, Doron

AU - Tam, Wayne

AU - Ruella, Marco

AU - Cerchietti, Leandro

AU - Rabadan, Raul

AU - Horwitz, Steven

AU - Inghirami, Giorgio

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

KW - CAR-T

KW - clonal evolution

KW - drug screenings

KW - microenvironment

KW - patient-derived tumor xenografts

KW - pre-clinical trials

KW - precision medicine

KW - repository

KW - stratification

KW - T cell lymphoma

UR - http://www.scopus.com/inward/record.url?scp=105001129663&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2025.102029

DO - 10.1016/j.xcrm.2025.102029

M3 - Article

AN - SCOPUS:105001129663

SN - 2666-3791

JO - Cell Reports Medicine

JF - Cell Reports Medicine

M1 - 102029

ER -

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

Abstract

Keywords

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