Over the past two decades, the immune system has attracted increasing attention for its role in fighting cancer.
As researchers have learnt more and more about the cancer-immune system interplay, several antitumor immunotherapies have become FDA-approved and are now regularly used to treat multiple cancer types.
Yet despite these advances, much remains unknown about how the immune system targets cancer — and about immunity in general, said Martin LaFleur, a postdoctoral fellow in the laboratory of Arlene Sharpe , chair of the Department of Immunology in the Blavatnik Institute at Harvard Medical School, USA.
CRISPR-based gene editing, in which scientists modify the genome using a tool developed just over a decade ago, has become a mainstay of biological discovery, providing relatively quick insight into the function of individual genes and targets for new therapies.
However, LaFleur said, this approach is not without challenges. Chief among them is that it is hard to modify immune cells without changing their biology, which hampers the ability to study immune cell behaviour in its full complexity in a living organism.
Now, LaFleur, Sharpe, and their team have succeeded in bypassing this hurdle by deploying CRISPR in a new way to study the function of immune genes.
Their work, described in two papers — one in Nature Immunology and one in the Journal of Experimental Medicine — could eventually yield insights about cancer immunology as well as about other diseases driven by immune system dysfunction.
“We decided to take a completely different approach for using CRISPR. Rather than directly modify the immune cells we’re interested in, we modified their precursors, the stem cells found in bone marrow that produce all immune cells. We removed those from mice and used CRISPR to knock out the genes we were interested in, and then replaced these stem cells in mice whose native bone marrow stem cells had been removed. We call this system CHimeric IMmune Editing, or CHIME.
“In an earlier study, we used CHIME to knock out a gene called Ptpn2, which has shown some promise for cancer immunotherapy, one of the focusses of the Sharpe Lab. When we deleted that one gene in a subset of immune cells known as CD8+ T cells, they became better cancer fighters,” said Martin LaFleur.
The aim with the Nature Immunology study was to see if CHIME can be modified to make it both more precise and more versatile.
“We’re hoping that this framework and CHIME will give researchers new tools to study immune cells in cancer or any other disease model of their choice, eventually leading to new immune-centred therapies,” said Martin LaFleur.
Source: Harvard Medical School
