Sirtuins and nuclear receptors in aging and age-associated diseases

National Institute Of Environmental Health Sciences

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Abstract

In the past year, our efforts were focused on understanding gene-environment interactions in regulation of anti-tumor immunity. Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, has been reported to repress cancer growth and improve cancer therapeutic responses in several pre-clinical models, most of which employed immunocompromised mice. However, how this dietary intervention impacts cancer progression in the context of the intact immune system with implications for immunotherapy, a backbone of modern cancer treatment, is unknown. In this study, we discovered that while inhibiting cancer growth in immunocompromised mice, dietary methionine restriction reduces T cell activation, exacerbates tumor growth, and impairs tumor response to immunotherapy in immunocompetent mice. Mechanistically, we show that the impact of dietary methionine restriction on tumor growth and anti-tumor immunity is partially dependent on gut microbiota-mediated non-cell autonomous activation of immune cells. Methionine restriction alters composition of gut microbiota and reduces microbial production of hydrogen sulfide. Fecal transplantation from methionine-restricted tumor-free animals is sufficient to suppress T cell activation and enhance tumor growth in tumor-bearing recipient mice. Conversely, dietary supplementation of a hydrogen sulfide donor or r precursor, or methionine, stimulates anti-tumor immunity and suppresses tumor progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency, and anti-tumor immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anti-cancer benefits of MR require careful consideration of both the microbiota and the immune system. A paper describing this study was published in Nature Metabolism (Ji et al., Nature Metabolism, 2023). This paper is highlighted by News & Views at Nature Metabolism (Joulia & Metallo, Nature Metabolism, 2023). DNASE1L3, an enzyme highly expressed in dendritic cells, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of anti-tumor immunity. In collaboration with Dr. Leping Li group at Biostatics & Computational Biology Branch, we recently identified DNASE1L3 as a new regulator of anti-tumor immunity and a tumor suppressor in colon cancer. In humans, DNASE1L3 is reduced in tumor-infiltrating dendritic cells, and this reduction is associated with poor patient prognosis and reduced tumor immune cell infiltration in many cancer types. In mice, Dnase1l3 deficiency in the tumor microenvironment enhances tumor formation and growth in several colon cancer models. Notably, the increased tumor formation and growth in Dnase1l3-deficient mice are associated with impaired anti-tumor immunity, including a substantial reduction of cytotoxic T cells and a unique subset of dendritic cells. Consistently, Dnase1l3-deficient dendritic cells directly modulate cytotoxic T cells in vitro. Collectively, our study unveils a previously unknown link between DNASE1L3 and anti-tumor immunity, and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anti-cancer therapy. A paper describing this study was published in JCI Insight (Li et al., JCI Insight, 2023). Additionally, we published two invited review articles (Fang & Li, Journal of Cellular Physiology, 2023; Fan & Li, Frontiers in Cell and Developmental Biology, 2023), and are currently working on two additional invited reviews (Fan & Li, Current Stem Cell Reports; Ji et al., Trends in Endocrinology and Metabolism).