Lymphoma accelerates T cell and tissue aging
Rebecca S. Hesterberg, Joshua Davis, Komal J Handoo, Aya G. Elmarsafawi, Anthony C. Augello, Chia‐Ho Cheng, Reginald Atkins, Dae Hyun Lee, Chunying Yang, Jiqiang Yao, Krishna Patel, Melanie Mediavilla-Varela, Javier Pinilla‐Ibarz, Carolina Soto-Palma, Frederick L. Locke, Xiaofei Song, Xuefeng Wang, Anders Berglund, Paulo C. Rodrı́guez, Gero Knittel, Ruth Flümann, Hans Christian Reinhardt, Timothy I. Shaw, Xiaoqing Yu, Laura J. Niedernhofer, John L. Cleveland
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.