Most colorectal cancers respond poorly to immunotherapy, leading scientists to believe these tumors display too few recognizable antigens for immune cells to target. But a new study published in Molecular & Cellular Proteomics challenges that assumption, showing that treatment-resistant colorectal tumors harbor tumor antigens capable of triggering immune recognition.
Although immunotherapy can be highly effective against colorectal tumors with microsatellite instability, or MSI, which tend to accumulate large numbers of mutations, about 85% of patients have microsatellite-stable, or MSS, tumors that respond poorly to treatment. Tumor antigens are cancer-specific peptides displayed on the cell surface that help the immune system recognize and attack cancer cells.
For years, scientists believed immunotherapy was largely ineffective against MSS tumors because they carry fewer mutations and were thought to display too few tumor antigens to trigger a strong immune response.
Pierre Thibault, a professor in the department of chemistry at the University of Montreal and senior author of the paper, has long been interested in how the immune system recognizes cancer cells at the molecular level. Building on prior findings that MSS tumors present a comparable number of tumor antigens to MSI tumors, his lab set out to investigate how the antigens presented by these two tumor types differ.
To do so, they analyzed tumors from 26 colorectal cancer patients using RNA sequencing and mass spectrometry. Together, these approaches helped identify potential tumor antigens and directly measure the peptides displayed by tumor cells.
They found that the key difference between MSI and MSS tumors lies not in the number of tumor antigens but in where those antigens originate. In contrast, MSS tumors tend to display peptides arising from silent DNA mutations generated through abnormal gene expression and genome reading. As a result, the tumor antigens presented by MSS tumors may appear less conspicuous to the immune system. Despite these differences, the researchers found that MSS tumor antigens are as capable of eliciting immune recognition as those in MSI tumors.
“Investigating these peptides was counterintuitive to a number of scientists at that time that we would be looking at these peptides,” Thibault said. “Later, however, it became clear that their production was a prevalent scheme taking place in tumor cells.”
These findings suggest new opportunities for targeting immunotherapy-resistant cancers, particularly through the development of cancer vaccines or personalized immunotherapy designed to recognize these overlooked antigens.
“We’re not there yet,” Thibault cautioned. “Translating the findings into treatments will be a long road. But we’re going to take it with small steps.”
If validated in future studies, these overlooked antigens could expand the number of colorectal cancer patients who benefit from immunotherapy.