Immunology of aging and immunotherapy of aging-associated diseases

National Institute On Aging

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Abstract

The immune system undergoes significant changes with aging, affecting both the function and subsets of B cells and T cells. These changes, in turn, influence the outcomes of aging-related pathologies and diseases. However, the mechanisms by which aging dysregulates these cells and increases prevalence of age-related diseases remain poorly understood. In my previous report, I have discussed the discovery of novel subsets of B cells, including cancer-induced Bregs (Olkhanud et al. Cancer Res, 2011; Bodogai et al., Cancer Res, 2013 and 2015; Ragganaud et al., Cancer Res. 2018) and macrophages derived from B cell precursors (Chen et al., Nature Comm, 2022) as the key facilitators of cancer metastasis. We also reported that aging associates with increase of novel pathogenic B cells (termed 4BL cells) (Lee-Chang et al., Blood, 2014; Lee-Chang et al., J. Immunol., 2016), which cause insulin resistance in aging (Bodogai et al., Science Transl. Med., 2018) as well as reduce some tumors via the induction of cytolytic CD8+ T cells. Here, I report that aged B cells also promote cancer in aging. We address this functional duality of B cells by comparing young (10-weeks old) and aged (18-20 months-old, C57BL/6) WT mice with or without orthotopic B16F10 melanoma or AT3 breast cancer, which respectively decreases or increases in aged mice. This study allowed us to find previously unknown subset of CXCR6+CD101+ CD39+ CD73+ CD8+ T cells (we termed DP8 cells, which markedly accumulates in aging alone). While the decrease of B16F10 tumor in aged mice we linked to 4BL cell-induced cytolytic CD8+ T cells, the increase of AT3 tumor was mediated by aged B cell-induced DP8 cells. Unlike B16F10 tumor, we found that tumors that increase in aged mice secrete CXCL16 chemokine and recruit DP8 cells via their CXCR6 receptor. This explains why tumors that progress in aged mice contained significantly more CD8+ T cells in the tumor tissue. Although CD8+ T cells are usually linked to antitumor benefit, the DP8 cells instead support tumor progression. Mechanistically, DP8 cells suppress antitumor effector cells by generating immunoregulatory adenosine from extracellular ATP using their surface-expressed CD39 and CD73. This tumor-enhancing mechanism of DP8 cells appears to be active in older humans, as we find DP8-like cells in various tumors, including in patients with late breast cancer onset. Overall, our experimentations with aged mice with and without various orthotropic cancers indicate that aging affects cancer outcome in a cancer- and immune cell- dependent manner requiring B cells. Unlike young hosts with cancer, the B-cell induced CD8+ T cells both inhibit and accelerate cancer progression in aged hosts. Our discovery of previously uncharacterized CD8+ T cell subset (DP8 cells) has significant clinical implications. DP8 cells actively supports cancer in aged hosts. Unlike age-associated exhausted CD8+ T cells, DP8 cells cannot be regulated by targeting checkpoint inhibitors. Instead, we show that tumor growth in aged mice can be blocked by targeting DP8 cell function or recruitment. We propose that this novel tumor-promoting role of CD8+ T cells needs to be considered in the development of therapeutics tailored for older people. This finding has been tentatively accepted for publication in Nature aging depending on a minor revision (Bodogai et al, 2025).