NK Cell (Natural Killer Cell) Attacking a Cancer Cell
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A new study by Yale School of Medicine researchers has identified a possible explanation for why some cancers don’t respond to immunotherapy. In an analysis of a Phase II trial investigating the immunotherapy drug pembrolizumab in 24 patients with endometrial cancer, the team found faulty DNA repair in tumors was a key factor in determining patient outcomes. The study was published in Cancer Discovery.

As the researchers explain, microsatellite instability (MSI) status is currently commonly assessed in patients with endometrial cancer, as it is a strong predictive marker for immunotherapy response. This study illuminates an additional dimension to MSI—mismatch repair deficiency—that further defines a patient subgroup that is very likely to respond to immunotherapy

“A key concept from our study is that it’s important to understand not just the state of a tumor as it presents in the clinic, but also its evolutionary journey. At present, tumors are coarsely classified by their features at the time of biopsy—for instance, the presence or absence of mismatch repair deficiency. Our study suggests that it is also valuable to investigate how the tumor got there, for instance, the mechanism of mismatch repair deficiency,” the study’s authors told Inside Precision Medicine.

The authors include: Alessandro Santin, a professor of obstetrics, gynecology, and reproductive sciences; Ryan Chow, an M.D./Ph.D. candidate working in Yale’s Department of Genetics and the Systems Biology Institute; and Eric Song, an ophthalmology resident and former Yale M.D./Ph.D. student.

Since immunotherapy can be very effective, but only helps a subset of patients, finding out who exactly benefits is a hot area of research and several other leads have already arisen, including a gene signature (in DDR2) for bladder cancer and an miRNA signature for lung cancer.

For this study, the Yale team focused on the failure of mismatch repair. When cells divide, errors often arise in their DNA. Through mismatch repair, certain proteins recognize and corrects errors in the DNA. A breakdown in this editing process occurs in many different types of cancer, however, leading to high mutation levels.

The team focused on the fact that mismatch repair deficiency can result from two distinct mechanisms. In one, mutations occur in the DNA repair machinery itself, leading to the production of defective repair proteins; in the second, production of the DNA repair machinery is halted entirely. In both cases, the tumors accumulate very high levels of mutations that would be expected to make them good candidates for immunotherapy.

“An analogy would be a dysfunctional toy factory,” Chow said. “Maybe the factory makes broken toys that don’t work, or the factory has no personnel and stops producing toys altogether. Either way, kids won’t be happy.”

In keeping with that analogy, the researchers found that tumors with defective DNA repair proteins had significantly better responses to immunotherapy than those in which the production of DNA repair proteins had been silenced. They found that these differences were ultimately linked to changes in the immune response mounted against each of the two classes of tumors.

“When it comes to immunotherapy, it seems that the journey—in this case, the underlying cause of mismatch repair deficiency—may be just as important as the destination,” Chow said.

Said Song, “The innovative use of clinical trial data can guide our understanding of how immunotherapy manipulates the immune system and ultimately improve how we treat patients.”

The team added, “Immunotherapy response is a highly complex issue involving multiple moving parts. As such, there are many additional mechanisms and biomarkers for immunotherapy response that will be uncovered in the coming years.”

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