Physician-scientist Omar Abdel-Wahab studies the relationship between splicing and cancer.
Like an invading army, cancer cells can have different modes of action. Some announce their arrival loudly while others wreak havoc by sneaking under the radar.
Immunotherapy drugs called checkpoint inhibitors work best against the less stealthy type. Their role is to take the natural brakes off the immune system and allow it to attack cancer. When cancer cells put out a bunch of flags, it’s easier for the immune system to find them. When the cells are hiding out, these drugs don’t work as well.
A collaborative team from Memorial Sloan Kettering and the Fred Hutchinson Cancer Research Center in Seattle has found a new way to put these flags on cancer cells and make them more visible to the immune system so that checkpoint inhibitor drugs work better. In mice, this approach appeared to be effective. Based on the findings, which were published June 24, 2021, in Cell, investigators are considering how this research could be applied to the development of new treatments.
“Immune checkpoint drugs have been a really revolutionary treatment for cancer,” says physician-scientist Omar Abdel-Wahab, who is a member of MSK’s Human Oncology and Pathogenesis Program and co-senior author of the study. “But not all patients benefit equally from these treatments. We want to find ways to make them work more broadly.”
Putting Flags on Cancer Cells
The flags added to the cells are called neoantigens. They are substances (antigens) that are new (neo) to the immune system. When immune cells come into contact with an antigen they’ve never encountered before, they are more likely to identify it as foreign and try to get rid of it.
Checkpoint inhibitors work by releasing a natural brake on your immune system so that immune cells called T cells recognize and attack tumors.
In 2014, MSK investigators published a groundbreaking study in the New England Journal of Medicine that found tumors with a greater number of mutations — which leads to the production of more neoantigens — respond better to checkpoint inhibitor drugs. This explained why cancers with a lot of mutations, like lung cancer and melanoma, are more likely to respond to these drugs. Cancers with fewer mutations, including breast cancer and most cases of colorectal cancer, are less likely to respond.
“The premise for this paper is that we could find a way to make cancer cells manufacture more of these foreign proteins so that immunotherapy drugs potentially would work better,” Dr. Abdel-Wahab says.
Changing How Proteins Are Made
In the new study, the researchers developed ways to prompt cancer cells to generate more neoantigens. They did this by manipulating a step of the protein manufacturing process called splicing. Splicing, which finalizes the blueprints by which proteins are made, determines which raw materials end up in the final protein and which get thrown away. The investigators discovered that by influencing the splicing process to create a new blueprint, they could coax cancer cells into creating more neoantigens.
The team used two different strategies to influence splicing. One was a drug that degrades a normal splicing factor. When the factor was degraded, it altered the blueprint for protein manufacturing, resulting in cells containing new proteins that they otherwise wouldn’t.
The other strategy was a drug that also altered the blueprint but in a different manner. This approach upsets the splicing process through a tactic called methylation. Again, the result was new and foreign proteins that the immune system detected as neoantigens.
When these drugs were added to cancer cells in a dish, they had no effect on their own. But when they were given to mice also receiving checkpoint inhibitors, they boosted the effectiveness of those drugs and led to better control of tumors. In some cases, drugs that altered splicing made cancer cells that are normally resistant to immune checkpoint blockade highly sensitive to immunotherapy.
“We did a number of experiments to show that the differences were due to the animals’ immune systems and that the foreign proteins were being attacked by immune cells,” says co-first author Sydney Lu, an MSK hematologist and medical oncologist who is a member of Dr. Abdel-Wahab’s lab.
Looking for Combination Approaches
Robert Bradley, a computational biologist at Fred Hutch and the paper’s co-senior author, contributed to the study by identifying many of the neoantigens that resulted from changes to the cells’ splicing mechanisms. Dr. Bradley and Dr. Abdel-Wahab have collaborated on the study of splicing for many years, including the early development of drugs that target splicing errors found in certain types of blood cancers.
The researchers say adding drugs that disrupt splicing factors could be useful for making checkpoint inhibitors work better on lung cancers, colon cancers, and melanomas that are less responsive. This approach could also be developed to treat types of cancer that generally don’t respond to immunotherapy at all.
“There’s also evidence that some of these splicing drugs have anticancer effects on their own,” Dr. Lu says. In fact, drugs that affect splicing through methylation are already being tested in clinical trials by themselves for a variety of cancers.
“It’s possible that combining these drugs with checkpoint inhibitors may be more effective, but it’s never been tested in humans before,” Dr. Abdel-Wahab adds. “It’s something that we plan to continue studying.”
