Dr. Connie Krawczyk
Rosalind and Morris Goodman Cancer Research Centre
Departments of Microbiology and Immunology and Physiology
The immune system has a remarkable capacity to detect eliminate tumour cells and protect from the development of cancer. Development of cancer, is in part, the break down of immune control mechanisms that are constantly putting pressure on tumour growth. We are studying the ability of tumour cells to suppress DC function and therefore anti-tumour immunity with the end goal of improving anti-tumour therapy through DC-targeted therapies or cancer vaccines.
The Krawczyk lab studies the molecular mechanisms regulating immune cell function, focused on dendritic cell (DC) and T cell activation, differentiation and function and how these are modified by the tumour microenvironment. The specific molecular mechanisms that we are interrogating can be broadly grouped into mechanisms that regulate gene expression (both transcription and translation) those which regulate cellular metabolism. We study these mechanisms in the context of both discovery research and health and disease including Leishmania infection, cancer immune-surveillance and vaccine development.
1. Gene Expression Programs in DCs
Transcriptional Regulation: We are studying the transcriptional repressor Mel- Bmi-like Ring finger protein (MBLR/PCGF6) and its role in regulating DC function. We first identified MBLR as a gene that was down-regulated upon activation of DCs. Since polycomb proteins are transcriptional repressors we hypothesized that MBLR/PCGF6 regulates DC activation and function.
We are also studying a group of transcriptional activators, the Notch family proteins. DCs express both Notch ligands and receptors and their role in DC biology is not well understood. It is thought that DCs deliver specific signals to T cells via the differential expression of Notch ligands DLL-1/4 and Jag1/2, however we have found that both Notch ligands and receptors regulate DC biology. Current studies aim to decipher the roles of Notch receptors and ligands in regulating DC activation, function and ability to communicate to T cells.
Translational Regulation: Since DCs are poised at the cellular level to respond to environmental threats, we hypothesize that DCs are also poised at the molecular level to acquire different activation phenotypes. mRNA expression analysis has revealed differences between differentially activated DCs however, the differences have been underwhelming. We hypothesize that there is an additional layer of regulation at the level of translation that facilitates immediate and differential activation of DCs. MicroRNAs have been identified as key regulators of translation allowing for dynamic regulation of gene expression. We are evaluating the role of specific microRNAs to regulate differential DC activation and to control gene expression programs in DCs.
2. Metabolic Pathways
Metabolic pathways regulate cellular energy and biosynthetic pathways, and are increasingly shown to regulate cellular function. A main focus of the lab is to study the role that cellular metabolism plays in DC activation and function. We are currently examining the metabolic profile of differentially activated DCs, and are beginning to determine whether differential use of metabolic pathways regulates their function. We are also examining whether DCs compete for nutrients or experience nutrient withdrawal in the tumour microenvironment and whether this affects their ability to promote anti-tumour immunity.