Meet Our Researchers
Our research group studies ways to enhance cancer immunotherapies, an emerging class of medicines that trigger the patient’s immune system to fight disease. Among the most successful cancer immunotherapies to date are checkpoint blockade inhibitors—which releases the immune system’s “brakes” in order to unleash an attack on tumor cells.
Checkpoint blockade inhibitors have been used very effectively in the clinic, underscoring their ability to induce an effective and lasting immune response against the tumor. However, only a small minority of patients responds well to checkpoint blockade inhibitors—many do not develop this antitumor immune response. Thus, our lab seeks to improve the drugs’ efficacy by combining them with other treatments. In particular, we are interested in therapies that shut down tumor cells’ “escape routes,” or the pathways that the cancer can use to evade the immune system.
First, we need to identify the genes that help cancer cells elude the human immune system, and we employed BroadIgnite funding to do so.
For the screen to work at scale, we first needed to create a pool of tumor cells that are each missing a unique gene. Fortunately, the genome-editing tool CRISPR-Cas9 has made this a relatively easy task and we can target 2,400 genes of interest at once with this strategy. Then, we injected these cells into mice, treated the mice with checkpoint blockade inhibitors and/or a general cancer vaccine that directs immune cells to the tumor, let the tumor grow for 14 days, and then removed it. We repeated this procedure in mice that lack immune responses. Our hypothesis was that the cells that didn’t have a key immune evasion gene should die off more quickly than cells that are missing a gene that isn’t involved in this pathway. We can determine which genes are missing in the surviving cells, and which genes play a role in immune evasion, by sequencing the genome of the surviving tumor cells and comparing them to tumors that were treated the same way in mice without functional immune systems.
In a pilot version of this screen, we looked for immune evasion genes in two different cancer cell lines that we then injected into mice, and identified genes that were already known to play a role in this pathway. These results validated our approach to this problem. We now plan to expand the screen into other cancer cell lines to discover their unique immune system vulnerabilities that could serve as targets for combination treatment with checkpoint blockade inhibitors.