In cancer immunotherapy, more isn't necessarily better

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Sep 14, 2023, 11:00 ET

COLD SPRING HARBOR, N.Y., Sept. 14, 2023 /PRNewswire/ -- DNA mismatch repair deficiency (MMRd) is a genetic condition often associated with colon cancer. It can happen in otherwise normal cells before cancer forms or after a tumor has already formed. The condition makes it hard for cells to correct mistakes that occur in DNA copying. This can lead to many mutations within tumors, or a high tumor mutation burden (TMB).

Isidro Cortés-Ciriano, a collaborator on the project, compares clonal and subclonal mutations to flashlights in a crowd. If all the flashlights shine with the same color, the signal is clear. “However, if each person in the crowd has a different colored flashlight, the light is less clear, and the signal becomes jumbled,” Cortés-Ciriano says. “Similarly, if cancer cells have different mutations, the signal is harder to make out and the immune system is not triggered.” Image: © Destrosvet – stoc

Peter Westcott studied MMRd tumors at the Massachusetts Institute of Technology along with MIT Professor David Jacks and Isidro Cortés-Ciriano, now a research group leader at the European Bioinformatics Institute. Above: MMRd lung cancer in a mouse 16 weeks after tumor initiation.

Some patients with high TMB respond well to immunotherapy, which uses the body's own immune system to fight cancer cells. But immunotherapy doesn't work for more than half of patients with advanced MMRd tumors. Now, research from Cold Spring Harbor Laboratory (CSHL) Assistant Professor Peter Westcott may help explain why.

As a postdoc at the Massachusetts Institute of Technology, Westcott and his colleagues created new mouse models to study differing responses to immunotherapy in colon and lung cancers from MMRd. The models had more mutations across their genomes to more accurately reflect tumors seen in human patients.

For years, researchers thought that more mutations in cells lead to a better immune response in cancer patients because their bodies have an easier time recognizing tumors. Some doctors see high TMB as an indication that immunotherapy will work well. In fact, even the FDA says high TMB can qualify patients for some immunotherapy treatments. But when Westcott's team tested their models for immune response, they found none. Westcott says:

"There's no question these tumors are DNA MMRd, yet they're not responding. That alone is a profoundly interesting negative result."

Westcott had a hypothesis. Although the tumors had many mutations, maybe they were too different from cell to cell to trigger an immune response. To test it out, the team isolated tumors with identical mutations in all cells, or clonal mutations, and tumors with identical mutations in only some cells, or subclonal tumors. They found that mice with clonal mutations responded to immunotherapy. Those with subclonal mutations did not.

The team also examined data from two small human clinical trials, and the hypothesis still held up. This remains the only human clinical trial data publicly available. Nevertheless, the potential clinical implications are staggering. Westcott says:

"If we can know if a patient's going to respond to therapy or not, that's extremely important information. Patients will have a much better sense of 'Is immune therapy right for me, or do I have to look elsewhere for treatment?'"

With more research, this finding could offer a new way to determine if immunotherapy is a viable treatment option for patients with MMRd.

About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,000 people including 600 scientists, students and technicians. For more information, visit www.cshl.edu

SOURCE Cold Spring Harbor Laboratory