A Korea-U.S. research team has developed a method to predict the response of an immune checkpoint inhibitor in gastric cancer patients.
According to Severance Hospital, Jung Jae-ho, a gastrointestinal surgery professor, discovered a gene signature that can predict the immune checkpoint inhibitor response in gastric cancer patients through a joint study with the Mayo Clinic and the University of Texas Southwestern Medical Center.
Gastric cancer accounts for the highest incidence rate among major cancer types in Korea. Physicians administer immune checkpoint inhibitors, a cancer treatment, which activates the patient's autoimmune system and prevents the body's immune cells from growing cancer cells to proceed with drug treatment. However, it is difficult to predict the response that appears in each patient.
Therefore, the research team entered the somatic mutation data of 6681 patients with 19 carcinomas announced by the Cancer Genome Atlas, a U.S. cancer big data platform, into NTriPath, a machine learning algorithm to analyze the cancer cell activation pathways seen only in gastric cancer.
NTriPath is a program that systematically analyzes large-scale genes to identify interactions between mutated genes and other genes jointly developed by Professor Jung and researchers at the Mayo Clinic.
As a result of the analysis, the team found that 32 gene signatures, including TP53, BRCA1, MSH6, and PARP1, affected cancer cell proliferation, apoptosis, damaged DNA repair, and mesenchymal origin cell pathways, correlated with immune checkpoint inhibitor responsiveness.
The research team applied the genetic analysis data of 567 patients who underwent gastric cancer surgery at Severance Hospital to check whether they can universally apply the analysis results to other gastric cancer patients.
Researchers confirmed that the cancer cell activation pathways were differently activated and were divided into two groups that showed different reactivity to immune checkpoint inhibitors.
In one sample group, they confirmed activation on the cellular pathway to repair damaged DNA and pathways related to inhibition of cancer cell proliferation and death. The treatment prognosis according to the immune checkpoint inhibitor was good.
However, in the other group, the team witnessed resistance to the checkpoint inhibitor, which activated the mesenchymal-origin cell pathway that triggers a tumor microenvironment where cancer cells protect themselves from immune cells.
They, therefore, concluded that activation of a cellular pathway to repair damaged DNA, inhibition of cancer cell proliferation, and the apoptosis-related pathway is a gene signature that identifies good responsiveness to immune checkpoint inhibitors. In contrast, activation of a cellular pathway of mesenchymal origin shows poor responsiveness, such as resistance toward the treatment.
"To enhance the effectiveness of checkpoint inhibitors and improve patient prognosis, we believe there is a need for a signature that can predict clinical effects," Professor Jung said. "Through the active pathway of mutant gene cancer cells identified through this study, we expect to establish a patient-specific strategy in treating gastric cancer."