Aging Induces CD8+ T Cells to Support Cancer Progression
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ABSTRACT:
PROVIDER: PRJNA1254283 | ENA |
REPOSITORIES: ENA
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Project description:The role of CD8+ T cell exhaustion in cancer in aging remains poorly understood. Although it is assumed that the age-related accumulation of exhausted, and thus dysfunctional, CD8+ T cells would increase tumor growth, in this study we provide an alternative paradigm: tumors in aged, but not young hosts, progress by actively using CD8+ T cells. These CD8+ T-cells are transcriptionally and epigenetically distinct and non-exhausted expressing the cell surface immunophenotype CXCR6+ CD39+ CD73+ CD101+ CD8+ (termed DP8). They accumulate in healthy aging, and at least in part, after induction with B cells presenting cognate antigens. Tumors that progress in aged mice recruit DP8 cells via the CXCL16/CXCR6 axis to suppress anti-tumor CD4+ T cells in an ADP/adenosine-dependent manner. This tumor-enhancing mechanism of DP8 cells appears to be active in older humans, as we detected DP8-like cells in various tumors, including late-onset breast cancer. We propose this novel tumor-promoting role of CD8+ T cells should be considered in the development of therapeutics tailored for the elderly as, targeting DP8 cell function or recruitment can reverse tumor growth in aged mice.
2025-07-22 | GSE295367 | GEO
Project description:Aging evokes immunosuppressive CD8+ T cells actively to support cancer
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Project description:Age-associated dysregulation and exhaustion of CD8+T cells is thought to impair antitumor responses and thus, increase cancer. Here we present evidence that CD8+T cells also actively promote tumor progression with age. We find that aging induces an expansion of a unique population of CXCR6+CD101+CD8+T cells expressing ectonucleotidases CD39 and CD73 (termed DP8 cells) via B cells presenting cognate antigen. We show that progressive (but not regressive) tumors in aged mice recruit these DP8 cells by expressing CXCL16 to suppress antitumor effector cellsusingthe ectonucleotidases. As a result, tumor growth in aged mice can be reversed by blockingthe function and/or recruitment of DP8 cells to tumors, while check-point inhibition with anti-PD1 Ab increases DP8 cells and drives tumor expansion.This tumor-enhancing mechanism of DP8 recruitment appears to be also active in older humans, aswe find DP8-like cells in various tumors, including late onset breast cancer.We propose that this novel tumor-promoting activity of CD8+T cells needs to be considered in the development of therapeutics tailored for the elderly.
2025-07-22 | GSE273565 | GEO
Project description:Progression of uterine aging in mice
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Project description:<p>The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving the changes characteristic of immune aging in humans remain poorly understood. One hallmark of immune aging is the loss of self-renewing naive cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we first inferred the transcription factor binding activities that maintain the naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we determined that BATF, ETS1, Eomes, and Sp1 govern transcription networks associated with specific CD8 T cell subset properties, including activation and proliferative potential. Extending our analysis to aged humans, we found that the differences between memory and naive CD8 T cells were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward a more differentiated pattern of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin openness at gene promoters, a phenomenon that appears to be due largely to a loss in binding by NRF1, leading to a marked drop-off in the ability of the naive cell to initiate transcription of mitochondrial genes. Our findings identify BATF- and NRF1-driven gene regulation as targets for delaying CD8 T cell aging and restoring T cell function.</p>
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Project description:Aging is a complex biological process that impacts various physiological functions, including the immune system. Our study investigated the impact of aging on CD8+ regulatory T cells (CD8+ Tregs), which showed a pattern of initial increase up to 12 months, then a decline by 24 months in a C57BL/6 mouse model, unlike memory T cells, which consistently increase with age. Functionally, CD8+ Tregs, irrespective of age, did not produce cytokines in response to TCR stimulation, highlighting a stark functional contrast with memory cells. However, upon IL-15 stimulation, CD8+ Tregs, unlike their memory cell counterparts, demonstrated enhanced cytokine production. Transcriptomic analysis revealed an abundance of Klrk1 (killer cell lectin-like receptor subfamily K member 1) gene transcripts in aging CD8+Tregs. Klrk1 gene encodes Natural Killer Group 2 Member D (NKG2D), an activating receptor NK cells express. This upregulation was specific to CD8+CD122hiLy49+ and absent in CD8+CD122hiLy49-. To explore this correlation further, we utilized a Klrk1-/- mouse and observed an increased CD8+Treg population, suggesting a potential negative regulatory role of NKG2D in CD8+Treg homeostasis. These findings provide critical insights into the aging immune system and underscore the importance of CD8+ Tregs in immune regulation and aging.
2025-03-20 | GSE252718 | GEO
Project description:T cells from several blood donors were separated in populations corresponding to CD8+ CD28+ and CD8+ CD28- surface markers. Total RNA extracts from cells were hybridized to MRC LNA microarray. Contrasts of interest were CD8CD28- minus CD8CD28+ (replicative aging) and CD8CD28+ (old donors) minus CD8CD28+ (young donors), which corresponds to chronological aging.
2010-04-19 | E-MEXP-2398 | biostudies-arrayexpress
Project description:Transcriptional Profile of CD8+ Tregs during aging
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