Ken Harder

The Harder lab has a long-standing interest in understanding the developmental programs guiding monocyte, macrophage, neutrophil and dendritic cell production from hematopoietic stem and progenitor cells. We are particularly interested in delineating the key phagocyte subsets, genes, and signalling pathways associated with chronic inflammatory diseases such as cancer, inflammatory bowel disease, heart disease, obesity, aging, and neurodegeneration, as recent studies by us and others have shown that phagocytes play key roles in each of these diseases.

Our studies have revealed the widespread impact that chronic inflammatory diseases have on these lineages of immune cells and our recent work has focused on understanding how key cytokines and signalling pathways control phagocyte fate and function. We contend that new treatments for these diseases will require a better understanding of phagocyte biology associated with disease, and will entail new strategies to target phagocytes with drugs, biologics, genetic modification strategies, or adoptive cell therapy approaches.

We employ a variety of cutting-edge techniques in our studies including systems biology single cell proteomic and transcriptomic technologies (CyTOF, scRNA-seq, CITE-seq) that rely on computational machine learning platforms to allow high dimensional, deep phenotyping of tens of thousands of individual cells in health and disease, simultaneously. Other technologies used in the lab include: genetically engineered mouse models, tissue culture/cellular immunology assays, flow cytometry, immunohistochemistry, molecular biology, CRISPR/Cas9 mutagenesis, siRNA technology, RNA-seq, new adoptive cell therapy approaches, and most recently lipid nanoparticle (LNP) mediated mRNA delivery in vivo.

High dimensional immunophenotyping of cancer.

One of the primary focuses of the lab is to better understand the tumour-induced immunosuppressive pathways that limit anti-tumour immunity. However, studying the immune system in the context of cancer is a daunting task. The immune system is comprised of dozens of different cell types, each characterized by an even greater number of cell phenotypes associated with distinct developmental or activation states spread across multiple tissue compartments. To address this complexity, we are using, and further developing, high dimensional single cell analytical approaches to simultaneously interrogate the immune cell subsets, signalling pathway activation patterns, and gene expression programs, associated with cancer. Our studies have identified new cytokine-driven immunosuppressive pathways as well as cancer-induced phagocyte subsets that we hypothesize lead to suppression of adaptive immunity against cancer. We are using spontaneous mutagen and chronic inflammation-induced colon cancer models as well as syngeneic melanoma, colon, breast, and ovarian cell line and organoids systems for these studies.

Understanding and harnessing the function of patrolling monocytes (pMos) in disease.

pMos are circulatory vessel migratory monocytes that play key roles in responding to tissue damage, heart disease and cancer. We are developing methods to grow pMos in the lab so that they can be harnessed for use following adoptive cell transfer to treat Alzheimer's disease and cancer. We have identified a key protein tyrosine kinase regulating pMos numbers, and are studying the gene expression and signalling pathways that this kinase regulates in pMos, to better understand and control pMos development, function and lifespan.

See Roberts et al, 2020 (https://pubmed.ncbi.nlm.nih.gov/32151196/) for an example of our work in this area.

Phagocyte immune checkpoint regulation in the control of metabolic disease, aging, and cancer.

Immune checkpoint blockade therapy has revolutionized the treatment of some cancers. These treatments arose from fundamental studies in mouse models of T cell signalling and the inhibitory receptor/ligand interactions governing T cell activation. However, inhibitory receptors are widely expressed across most immune cell lineages and are particularly abundant on monocytes, macrophages and dendritic cells. Our lab is studying how changes in the balance of stimulatory and inhibitory signalling impacts phagocyte function in cancer and metabolic diseases. For example, we know that the SIRPa/CD47 inhibitory receptor/ligand pair is an important regulator of macrophage phagocytosis of stressed, necrotic and tumour cells. We previously identified a key regulator of this receptor and are exploring how this pathway and others can be targeted to improve cancer immunotherapy and phagocyte targeting of stressed, senescent, or necrotic cells. We propose that future drugs targeting myeloid cell immune checkpoints will greatly improve our ability to treat chronic inflammatory diseases.

See Harder et al, 2001 (https://pubmed.ncbi.nlm.nih.gov/11672542/) for an example of our early work in this area.

Improving LNP technology to enhance phagocyte function in disease and to develop new cancer vaccines.

LNP-mRNA vaccines from BioNtech/Pfizer and Moderna have been instrumental in reversing the course of the COVID-19 pandemic and have clearly shown the power of this technology against infectious disease. Together with our collaborators in the Nanomedicines Innovation Network (NMIN- https://www.nanomedicines.ca), we are working to develop new and improved LNP formulations encapsulating designer mRNAs to improve immune system function in cancer and other chronic inflammatory diseases. We are using high throughput microfluidic, single cell multiplexed transcriptomic and proteomic platforms, to screen libraries of distinct LNP formulations to identify those with enhanced immune subset tropisms and regulatory features. We envision that this project will lead to new nanomedicines and improved vaccine designs.