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Deciphering the effects of metabolic regulation on the function of innate-lymphoid cells in hormone-dependent cancers

In the past decades, various approaches have been implemented to improve cancer treatments. However, the efficacy of therapies remains variable among patients and the underlying causes are yet to be elucidated. One aspect that gained increasing attention is the impact of metabolic barriers in the tumor microenvironment (TME) on immune cell function. Thus, understanding how metabolic reprogramming leads to an immunosuppressive TME is essential. Innate lymphoid cells (ILCs) are a tissue-resident population crucial in host defense and the maintenance of metabolic homeostasis. Depending on the type of cancer, ILCs have been shown to have both tumor-promoting and tumor-suppressive functions. In this project we aim to focus on the role of ILCs in hormone-dependent cancers (prostate and breast), that are known to undergo major metabolic changes compared to their tissue of origin during tumor progression.

Understanding the role of diet-derived metabolites on anti-viral and anti-tumor responses during influenza and in lung cancer

Host, diet- and microbial-derived metabolites directly influence human health by shaping host metabolism and regulating immune cell development and function. This project aims to understand the direct and indirect effects of nutrients in cancer and infection following the idea that respiratory viral infections induce a transient state of fasting and ketogenesis. Increased level of β-hydroxybutarate have been reported in lung cancer patients, however the effects of tumor growth on this metabolic axis is currently unknown. Previous studies in our lab suggest that liver-derived ketone bodies produced in the context or infection-induced anorexia can directly promote protective immune responses.

Using a discovery approach, we aim to expand on this concept, and identify host-, diet- and microbial-derived metabolites produced or diminished in infection and cancer and study their ability to affect the immune system or other tissue components. Preliminary data suggest that an increased abundance of certain microbiota-derived metabolites could accelerate anti-viral immunity. Such metabolites could be directly harnessed as small molecule modulators to either boost anti-viral or anti-tumor immune responses or to prevent or treat infection-induced pathologies.

Investigating the effects of lipid-mediated metabolic reprogramming on NK cells

Metabolic reprogramming of the tumor microenvironment (TME) is a key determinant of tumor-infiltrating immune cell dysfunction. Perturbations in lipid metabolism have been inherently linked to prostate cancer pathogenesis and disease progression. Natural killer (NK) cells can infiltrate prostate tumors and play an integral role in tumor immunosurveillance. Dysregulation of lipid metabolism has been associated with impaired NK cell activity, resulting in enhanced tumor growth and an increased rate of metastasis. However, the mechanisms underlying the metabolic reprogramming and functional impairment of NK cells by lipids remain poorly understood. 

This project aims to decipher the mechanisms by which the lipid droplets regulate the phenotype and function of NK cells within the tumor microenvironment.