Lymphoma accelerates T cell and tissue aging

Rebecca S Hesterberg¹, Joshua T Davis², Komal J Handoo³, Aya G Elmarsafawi³, Anthony C Augello³, Chia-Ho Cheng⁴, Reginald Atkins⁵, Dae Hyun Lee⁶, Chunying Yang³, Jiqiang Yao⁴, Krishna R Patel³, Melanie Mediavilla-Varela⁷, Javier Pinilla-Ibarz⁷, Carolina Soto-Palma⁸, Frederick L Locke⁵, Xiaofei Song², Xuefeng Wang², Anders E Berglund⁹, Paulo C Rodriguez¹⁰, Gero Knittel¹¹, Ruth Flümann¹², Hans Christian Reinhardt¹³, Timothy I Shaw², Xiaoqing Yu², Laura J Niedernhofer⁸, John L Cleveland¹⁴

Affiliations

¹ Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: rebecca.hesterberg@moffitt.org.
² Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
³ Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁴ Biostatistics & Bioinformatics Shared Resource, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁵ Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁶ Department of Internal Medicine, Division of Cardiovascular Disease, University of South Florida, Tampa, FL 33602, USA.
⁷ Department of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁸ Institute on the Biology of Aging & Metabolism, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁹ Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
¹⁰ Department of Immunology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹¹ Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK Partner Site Essen/Düsseldorf, University Hospital Essen, Essen, Germany; Center for Molecular Biotechnology, University Hospital Essen, Essen, Germany.
¹² Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
¹³ Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK Partner Site Essen/Düsseldorf, University Hospital Essen, Essen, Germany; Center for Molecular Biotechnology, University Hospital Essen, Essen, Germany; Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
¹⁴ Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: john.cleveland@moffitt.org.

PMID: 40845845
DOI: 10.1016/j.ccell.2025.07.023

Free article

Lymphoma accelerates T cell and tissue aging

Rebecca S Hesterberg et al. Cancer Cell. 2025.

Free article

. 2025 Aug 18:S1535-6108(25)00329-0.

doi: 10.1016/j.ccell.2025.07.023. Online ahead of print.

Authors

Affiliations

¹ Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: rebecca.hesterberg@moffitt.org.
² Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
³ Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁴ Biostatistics & Bioinformatics Shared Resource, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁵ Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁶ Department of Internal Medicine, Division of Cardiovascular Disease, University of South Florida, Tampa, FL 33602, USA.
⁷ Department of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
⁸ Institute on the Biology of Aging & Metabolism, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁹ Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
¹⁰ Department of Immunology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹¹ Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK Partner Site Essen/Düsseldorf, University Hospital Essen, Essen, Germany; Center for Molecular Biotechnology, University Hospital Essen, Essen, Germany.
¹² Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
¹³ Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany; West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK Partner Site Essen/Düsseldorf, University Hospital Essen, Essen, Germany; Center for Molecular Biotechnology, University Hospital Essen, Essen, Germany; Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
¹⁴ Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: john.cleveland@moffitt.org.

PMID: 40845845
DOI: 10.1016/j.ccell.2025.07.023

Abstract

The combined effects of aging and cancer on immune cells were investigated in young versus aged mice harboring B cell lymphoma, and in T cells from young and aged B cell lymphoma patients. These analyses revealed that lymphoma alone is sufficient to trigger transcriptional, epigenetic, and phenotypic alterations in young T cells that manifest in aged T cells. In contrast, aged T cells are largely resistant to lymphoma-induced changes. Pathway analyses revealed open chromatin regions and genes controlling iron homeostasis are induced by both lymphoma and aging, and lymphoma-experienced and aged T cells have increased iron pools and are resistant to ferroptosis. Furthermore, both aged and lymphoma-experienced T cells have defects in proteostasis. B cell lymphoma also accelerates aging of other tissues, as evidenced by elevated expression of Cdkn2a and Tnfa. Finally, some lymphoma-induced aging phenotypes are reversible whereas others are fixed, indicating opportunities for improving some cancer-associated aging comorbidities.

Keywords: B cell lymphoma; NK cell; T cell; aging; ferroptosis.

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Conflict of interest statement

Declaration of interests F.L.L. has served or is serving in an advisory role for A2, Allogene, Amgen, Bluebird Bio, BMS, Calibr, Caribou, Cowen, EcoR1, Gerson Lehrman Group (GLG), Iovance, Kite Pharma, Janssen, Legend Biotech, Novartis, Sana, Umoja, and Pfizer. L.J.N. serves an advisory role for Innate Biologics and Itasca Therapeutics. J.P-I. has served or is serving in advisory role for Beigene, Astra-Zeneca, Janssen, BMS, Precigen and Abbvie. H.C.R. received consulting and lecture fees from Abbvie, Roche, KinSea, Vitis, Cerus, Lilly, Novartis, Takeda, AstraZeneca, Vertex, and Merck. H.C.R. also received research funding from AstraZeneca and Gilead Pharmaceuticals. H.C.R. is a co-founder of CDL Therapeutics GmbH.

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Lymphoma accelerates T cell and tissue aging

Affiliations

Lymphoma accelerates T cell and tissue aging

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

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