LAB IN THE NEWS
Wistar Institute finds its first Caspar Wistar Fellow in Canada
The Wistar Institute has appointed its first Caspar Wistar Fellow. The honor went to Rahul Shinde, whose research is focused on the role specialized cells known as macrophages play as a front-line defense system for the body's immune system.
The Shinde Laboratory
The tumor microenvironment (TME), consisting of stroma, immune cells and extracellular matrix, is a key determinant of cancer initiation, progression and resistance to therapies. Understanding the heterogeneity of the TME and the molecular mechanisms contributing to immune responses is critical to enhance immunotherapy and prevent/overcome resistance. Macrophages are major components of the TME and regulate inflammation, angiogenesis, extracellular matrix remodeling, and T-cell suppression. Alterations in the metabolism of macrophages affect their function. Research in the Shinde lab focuses on characterizing the molecular mechanisms underlying metabolic plasticity in macrophages during tumorigenesis.
Commensal microbiota residing in the gut can also modulate the TME and affect tumor progression and response to therapy. Host, dietary and environmental factors contribute to changes in the microbiome. The lab is also interested in characterizing the healthy/symbiotic or disease-modulating/dysbiotic microbiome and its crosstalk with immunometabolism during disease development.
The Shinde lab investigates amino acid metabolism in regulation of immunity. Metabolic profiling has identified increased plasma levels of branched-chain amino acids (BCAA) in a variety of disorders including pancreatic cancer. BCAA are a class of essential amino acids that can influence immune functions and disease outcome. Dietary intake represents a major source for BCAA in the circulation, but it is unclear what contributes to altered levels of BCAAs and their effects on disease onset and progression.
BCAA metabolism is transcriptionally controlled by Krüppel-like factors (KLFs). KLFs are DNA-binding transcriptional regulators known to control multiple metabolic events including glycolysis, oxidative phosphorylation, fatty acid oxidation, and degradation of amino acids. Alterations in KLF signalling and post-translational modifications are linked to monocyte differentiation, macrophage polarization, angiogenesis, and inflammation. However, the biologic role of KLFs in tumor immunology is not well understood. Mechanistic and functional characterization of the KLF biology and the BCAA pathway contributing to the altered metabolic state of macrophages will provide significant insight into the behavior of macrophages in the TME.
The lab is interested in evaluating the functional implications of KLF biology and BCAA catabolism in macrophages driving tumor progression and resistance to therapy. These studies will have potential clinical impact providing insights into previously unsuspected targets for therapy.
Roux, C., Jafari, S.M., Shinde, R., Duncan, G., Cescon, D.W., Silvester, J., Chu, M.F., Hodgson, K., Berger, T., Wakeham, A., Palomero, L., Garcia-Valero, M., Pujana, M.A., Mak, T.W., McGaha, T.L., Cappello, P., Gorrini, C. “Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1.” Proc Natl Acad Sci U S A. 2019 Feb 15. pii: 201819473. doi: 10.1073/pnas.1819473116. [Epub ahead of print]
Shinde, R., McGaha, T.L. ”The Aryl Hydrocarbon Receptor: Connecting Immunity to the Microenvironment.” Trends Immunol. 2018 Dec;39(12):1005-1020. doi: 10.1016/j.it.2018.10.010. Epub 2018 Nov 5.
Shinde, R., Hezaveh, K., McGaha, T.L., et al. “Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans.” Nat Immunol. 2018 Jun;19(6):571-582. doi: 10.1038/s41590-018-0107-1. Epub 2018 May 14.
Sharma, M.D., Shinde, R., Munn, D.H., et al. “The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment.” Sci Adv. 2015 Nov 6;1(10):e1500845. doi: 10.1126/sciadv.1500845. eCollection 2015 Nov.
Shinde, R., Shimoda, M., McGaha, T.L., et al. “B Cell-Intrinsic IDO1 Regulates Humoral Immunity to T Cell-Independent Antigens.” J Immunol. 2015 Sep 1;195(5):2374-82. doi: 10.4049/jimmunol.1402854. Epub 2015 Jul 27.