Aging evokes immunosuppressive CD8+ T cells actively to support cancer
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PROVIDER: PRJNA1142422 | ENA |
REPOSITORIES: ENA
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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:Aging Induces CD8+ T Cells to Support Cancer Progression
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Project description:CD105+ fibroblasts support an immunosuppressive niche in women at high risk of breast cancer initiation
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Project description:Background: Aging is the greatest risk factor for breast cancer, and although epithelial cells are the source of carcinomas, epithelial changes alone do not fully explain cancer susceptibility. Fibroblasts and macrophages are key stromal constituents around the cells of origin for cancer in breast tissue. With age, macrophages surrounding terminal ductal lobular units (TDLUs) become increasingly immunosuppressive. CD105+ fibroblasts intercalate within TDLUs, drive luminal differentiation, and give rise to immunosuppressive cancer-associated fibroblasts in other tissues. We propose that differences in fibroblasts are a crucial component of the stroma that shapes cancer susceptibility. Methods: Primary fibroblast cultures were established from prophylactic and reduction mammoplasties from women ranging in age from 16 to 70 years and breast cancer risk (BRCA1 mutation carriers). Growth characteristics, transcriptional profiles, differentiation potential, and secreted proteins were profiled for fibroblast subtypes from diverse donors. Co-cultures with fibroblasts, monocytes, macrophages, and T cells were used to ascertain the functional role played by CD105+ fibroblasts in immune cell modulation. Results: We found that peri-epithelial CD105+ fibroblasts are enriched in older women as well as women who carry BRCA1 mutations. These CD105+ fibroblasts exhibit robust adipogenesis and secrete factors related to macrophage polarization. Macrophages cocultured with fibroblasts better maintain or enhance polarization states than media alone. CD105+ fibroblasts increased expression of immunosuppressive macrophage genes. CD105+ fibroblasts supported anti-inflammatory macrophage-mediated suppression of T cell proliferation, whereas CD105− fibroblasts significantly reduced the suppressive effect of anti-inflammatory macrophages on T cell proliferation. Conclusions: Establishment of a coculture system to dissect the molecular circuits between CD105+ fibroblasts and macrophages that drive immunosuppressive macrophage polarization has broad utility in understanding mammary gland development and events that precede cancer initiation. CD105+ fibroblasts and macrophages may coordinate to suppress immunosurveillance and increase breast cancer susceptibility.
2025-05-16 | GSE296967 | GEO
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.
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2025-01-06 | GSE275168 | GEO
Project description:With aging, the immune system undergoes immunosenescence, accompanied by chronic low-grade inflammation (inflammaging). Balanced immunity relies on effector and regulatory cells, with myeloid-derived suppressor cells (MDSCs) playing a key regulatory role. MDSCs, a heterogeneous population of immature myeloid cells, develop under inflammatory conditions and primarily suppress T cell activity. The age-dependent increase in myelopoiesis and inflammation, along with reduced immune reactivity, suggests that changes in the number and function of regulatory cells, such as MDSCs, might strongly contribute to age-related modifications of immune responses. While studies in mice have demonstrated an age-related increase in MDSC numbers, human studies have predominantly focused on cancer patients, making it challenging to separate the effects of aging and cancer on MDSC induction. Therefore, we analyzed MDSC increases in older individuals without a history of cancer. Furthermore, we excluded patients with neurodegenerative, cardiovascular or autoimmune diseases. We found a significant increase in circulating MDSCs in old donors. In addition, in vitro generated, blood-derived MDSCs from old donors exhibited enhanced immunosuppressive and Th2 polarizing capacity. RNA sequencing indicated age-related metabolic changes. These findings highlight that age-related changes in MDSCs contribute to dysregulated immune functions during aging.
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