Checkpoint inhibitor drugs that stimulate the immune system have become a growing success story in the treatment of some cancers. But about half of patients whose tumors are marked by a large number of mutations from so-called mismatch repair genetic deficiency fail to respond to the drugs.
Researchers from the Johns Hopkins Kimmel Cancer Center, its Bloomberg~Kimmel Institute for Cancer Immunotherapy, and the Memorial Sloan Kettering Cancer Center say they have found a potential explanation for the failures.
Mismatch repair deficiency refers to a characteristic of some cancer cells that create a large number of mutations, or changes, in certain genes when their mismatch repair proteins are unable to correct mistakes made when DNA is copied and passed on to daughter cells. Tumor cells with many such mutations create what is known as microsatellite instability and a worsening inability to correct those DNA mistakes. And, because defective genes can cause both inherited and noninherited (or sporadic) forms of cancer, they are used as biomarkers for diagnostic screening and chemotherapy treatment planning.
In a new study of such tumors in mice and humans, the investigators say they discovered that the tumors most likely to respond to immunotherapy have a higher degree or intensity of microsatellite instability (MSI) than tumors with lower MSI, meaning the former tumors possess a higher degree of DNA alterations after repeated cell divisions over time.
In particular, the researchers report, they have a higher amount of insertion/deletion, or indel, mutations of the DNA building blocks compared to other tumors. Indel mutations involve a series of nucleotides, or genetic “letters,” either inserted into the genetic code or removed during cell division. They can potentially generate neoantigens, or new proteins in cancer cells that the immune system can recognize and destroy.