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.
Gauri Mirji, Ph.D.
A postdoctoral fellow position is available in the Shinde lab. Applicants should have or be close to obtaining their doctoral degree (or equivalent) in biomedical sciences or a related field.
The ideal candidate will have experience in immunology, cancer biology, macrophage function, mouse modeling, and relevant experience with the gut microbiome. Interested applicants should submit a cover letter summarizing past and future research interests, CV, two references, and reprints of two supporting publications (optional) to Dr. Shinde at rshinde@Wistar.org
The first project in our laboratory seeks to understand how host metabolism impacts disease progression and therapy resistance in pancreatic cancer. Tumor metabolism in pancreatic cancer is known to be dysregulated both in neoplastic and in tumor microenvironment (TME) cells, significantly altering immune responses. Metabolic profiling has identified increased plasma levels of branched-chain amino acids (BCAA) in a variety of disorders including pancreatic ductal adenocarcinoma (PDAC). Our new work shows that transcriptional regulators of BCAA oxidation, such as Krüppel-like factors (KLF), are linked to the phenotype of tumor-associated macrophages (TAMs). This project seeks to elucidate the functional implications of KLF biology and BCAA catabolism in TAMs for driving tumor progression and resistance to therapy.
The second project in our lab investigates the connections between gut microbial metabolic pathways and therapy response. Immune responses can be altered by metabolic processes occurring outside the TME, for example, by metabolites produced by gut bacteria. Recent studies show that particular species of gut bacteria influence PDAC outcomes and response to therapy and do so by altering innate and adaptive immunity; however, the specific mechanisms are not clear. This project seeks to identify the metabolic pathways by which the gut microbiome influences antitumor immune responses, impacting PDAC burden and therapy response.
Our studies will have potential clinical impact providing insights into previously unsuspected targets for cancer therapy. More broadly, we expect our findings to shed light on how diet, host metabolism and gut microbiome are linked in shaping immune function and therapy response.
Roux, C., Jafari, S.M., Shinde, R., Duncan, G., Cescon, D.W., Silvester, J., Chu, M.F., Hodgson, K., Berger, T., Wakeham, A., et al. “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., Halaby, M.J., Kloetgen, A., Chakravarthy, A., da Silva Medina, T., Deol, R., Manion, K.P., Baglaenko, Y., Eldh, M., 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., McGaha, T.L., Huang, L., Holmgaard, R.B., Wolchok, J.D., Mautino, M.R., Celis, E., Sharpe, A.H., Francisco, L.M., 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., Chaudhary, K., Liu, H., Mohamed, E., Bradley, J., Kandala, S., Li, X., Liu, K., 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.
Zachary Schug, Ph.D.
Assistant Professor, Molecular & Cellular Oncogenesis Program, The Wistar Institute Cancer Center