Lymphoma accelerates T cell and tissue aging

  • Cancer Cell. 2025 Aug 18:S1535-6108(25)00329-0. doi: 10.1016/j.ccell.2025.07.023.
Rebecca S Hesterberg  1 ,  Joshua T Davis  2 ,  Komal J Handoo  3 ,  Aya G Elmarsafawi  3 ,  Anthony C Augello  3 ,  Chia-Ho Cheng  4 ,  Reginald Atkins  5 ,  Dae Hyun Lee  6 ,  Chunying Yang  3 ,  Jiqiang Yao  4 ,  Krishna R Patel  3 ,  Melanie Mediavilla-Varela  7 ,  Javier Pinilla-Ibarz  7 ,  Carolina Soto-Palma  8 ,  Frederick L Locke  5 ,  Xiaofei Song  2 ,  Xuefeng Wang  2 ,  Anders E Berglund  9 ,  Paulo C Rodriguez  10 ,  Gero Knittel  11 ,  Ruth Flümann  12 ,  Hans Christian Reinhardt  13 ,  Timothy I Shaw  2 ,  Xiaoqing Yu  2 ,  Laura J Niedernhofer  8 ,  John L Cleveland  14
Affiliations
  • 1. Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: [email protected].
  • 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: [email protected].
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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