Immunology of aging and immunotherapy of aging-associated diseases

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

The role of B cells in cancer and aging-associated pathologies remains poorly understood. Previously we reported that cancer converts B cells to generate immunoregulatory B cells (Bregs) (Olkhanud et al. Cancer Res, 2011; Bodogai et al., Cancer Res, 2013 and 2015). We also found that to generate Bregs, cancer uses B-cell precursors. To do this it first recruits B-cell precursors from the bone marrow (Ragganaud et al., Cancer Res. 2018). Now we reports that some of these B-cell precursors are converted into macrophage-like cells to mediate its metastasis. This process requires cancer cells to secrete M-CSF. This study was recently published from my group (Chen et al., Nature Comm, 2022). Previously I reported the discovery of uniquely activated innate B1 B cells, termed 4BL cells, which accumulate in aging of humans, primates, and mice (Lee-Chang et al., Blood, 2014; Lee-Chang et al., J. Immunol., 2016). We reported that their activation is triggered by dysbiosis of gut microbiota in aging. In particular, the loss of beneficial commensals, such as Akkermansia muciniphila (Akk), initiates a chain of inflammatory events that leads to gut leakiness and consequent low levels of systemic inflammation. It causes activation and recruitment of monocytes in the omentum, where they convert B1a B cells into potentially 4BL cells. We also linked 4BL cells to upregulation of insulin resistance in elderly mice and macaques (Bodogai et al., Science Transl. Med., 2018). Importantly, we devised several strategies that block the induction of 4BL cells and thus insulin resistance in aged hosts. These strategies that block MO activation, accumulation of 4BL cells, and reverses insulin resistance in aged hosts include A, antibody-based depletion of monocytes or B cells , and B, a short-term supplementation with Akk. I should point out that consistent with these results and findings from others, Akk is now being widely considered as a magic bullet in therapy of metabolic syndromes and inflammatory pathologies of the elderly. However, safety and clinical consequence of its long-term use remain unknown. In 2019, I proposed that although our brief supplementation with Akk is beneficial, its benefit will either disappear or be even harmful after long-term use in aged hosts. My main hypothesis was that if the Akk loss in aging is driven by immune response, a repeated supplementation with Akk will exacerbate the Akk loss due to activation of anti-Akk immune response. To test this idea, in 2019/2020 we initiated a longitudinal study by orally gavaging middle-aged female and male mice with Akk for more than one year. Although the study was significantly affected by the COVID pandemic, we were able to complete its experimental part around end of 2021. The study has generated a wealth of data (microbiome sequencing, immune and metabolic profiling, insulin resistance, survival and etc), which is being analyzed in collaboration with Dr. Trinchieris group (NCI). Overall, we have achieved objectives of the study. Because the COVID pandemic interrupted collection of some key samples, recently we had to redo some experiments and sequence additional mouse microbiota to be used as controls. Thus, expected time for submission of results for publication early 2024. The role of dysregulation of immune cells in cancer outcome in aging remains poorly understood. Our experimentations with aged mice with various orthotropic cancers indicate that aging significantly affects cancer outcome in cancer- and immune cell- dependent manner. In aged mice, cancer progression and metastasis decreases, increases, or stays the same as in young hosts. By performing an extensive profiling of immune cells of these mice, particularly young and old mice with orthotopic melanoma or breast cancer, we found that the differential cancer outcome in aging is actively controlled by B cells. Underscoring previously unknown function and thus underscoring their importance, our results indicate that aged B cells regulate activation, exhaustion, and recruitment of CD8 T cells in the tumor. Importantly, this phenomenon is not detected in young hosts, implying that it is a unique feature of aging. I plan to report this study for publication by November of 2023. My collaboration with with Drs. Stack (U. Notre Dame) amd Annunziata (NCI) progressing well. Our paper on the importance of aging in metastasis of ovarian cancer is recently published (Harper et al., Aging and Cancer, 2022). Despite COVID-19 pandemic, which caused marked loss of opportunities, time and resources, we generated novel data with significant scientific and clinical relevance.