This week we profile a recent publication in Nature Communications from Dr. Govinda Sharma
(pictured) in the laboratory of Dr. Robert Holt at the Michael Smith Genome Sciences Centre.
Can you provide a brief overview of your lab’s current research focus?
The Holt Lab is located at Canada’s Michael Smith Genome Sciences Centre at BC Cancer (GSC). The group uses cutting edge tools and methodologies to investigate the biology of cancer from several different angles. Focusing on the immune system, the group has used deep sequencing to survey T cell repertoire diversity at the resolution of individual clonotypes and are now using these methodologies to explore the role of T cells in cancer. They are also working to develop cancer immunotherapies using engineered T cells to selectively deliver cytotoxic payloads to bolster the anti-cancer immune response and to enhance tumour cell killing. The group employs their expertise in DNA sequencing and computational analyses to investigate the role of infectious agents in cancer development and were the first to demonstrate a strong link between the pathogen Fusobacterium nucleatum and colorectal cancer. Finally, they apply deep sequencing technologies to identify the spectrum of mutations in various cancer types, with a particular focus on tumour evolution and the identification of antigens for cancer vaccines.
What is the significance of the findings in this publication?
Lying in wait within our immune systems are specialized cells called cytotoxic T cells (or CTLs), patrolling our bodies, searching for and eliminating disease. Scientists have shown that we can harness the search-and-destroy functions of CTLs to help our bodies fight off cancer, but finding these cancer-fighting cells is like searching for a needle in a haystack. A new method developed in the laboratory of Dr. Rob Holt, a Distinguished Scientist at the GSC, has made finding these cancer-fighting CTLs a lot easier.
The method, which was developed by Dr. Govinda Sharma during his PhD work in Dr. Holt’s lab, takes advantage of the CTLs’ granzyme-mediated cell killing to identify disease antigens. To do this, the scientists generate a library of cells, each displaying a different antigen. Only a small fraction of these antigens will signal disease, and the goal is to find them. They mix the cell library together with CTLs and wait. Within a couple of hours, the CTLs will have found their targets and will have released their arsenal of perforin and granzymes. Once the target cells have been invaded by granzymes, they light up in a way that can be detected by specialized laboratory instruments. Then, using DNA sequencing, the team can determine precisely which antigens signaled the presence of disease.
This method greatly enhances our ability to rapidly and comprehensively survey the interactions between CTLs and their target cells. This is a major improvement over the conventional methods used previously as it allows scientists to screen hundreds to thousands of times more potential antigens in parallel.
What are the next steps for this research?
Dr. Sharma, who is now a post-doctoral fellow at the GSC, plans to take the method he developed during his graduate work, which was published this week in Nature Communications, to start a biotech company. Offering this method to cancer researchers and industry scientists will greatly enhance our ability to rapidly identify target antigens, helping pave the way towards safe and effective CTL-mediated immunotherapies and cancer vaccines.
This work was funded by:
The Natural Sciences and Engineering Research Counsel of Canada, Genome Canada, Genome BC, the BC Cancer Foundation, Canada’s BioCanRx Network Centre of Excellence, and the National Cancer Institute of the US National Institutes of Health.
To find out more about the Holt lab, visit their website and follow them on Twitter:
