In a report, March 6 in Cancer Discovery , that has been observed that MSI-high or immune-infiltrated tumors have evolved mutations that confer resistance to recognition by the immune system in untreated samples (ie, immunoediting). "
Frequent immunoediting helps microsatellite-instability-high (MSI-high) colorectal cancer evades the immune system, according to new genomic analysis. "Here, we demonstrate that there are other factors besides mutation load affecting T-cell infiltration in both MSI-high and MSS," noted Dr. Catherine S. Grasso and colleagues of the University of California.
"Specifically, MSI-high tumors frequently underwent immunoediting through complete disruption of both alleles of key genes in the MHC-antigen presentation pathway and that both MSS and MSI-high cancers have lower T cell infiltration when molecular events that up-regulate the WNT pathway are present, "noted Grasso.
"We showed that Cancer and the immune system are at an impasse, but cancer evolves to develop resistance to the immune system by knocking out how it is recognized," noted Grasso.
The work was based on analysis of more than 1,200 colorectal cancer cases. MSI-high colorectal cancer, which comprised 15% of the samples, has been shown to respond to immune checkpoint blockade, whereas the much more common microsatellite-stable (MSS) disease usually does not.
Analysis of the 179 MSI-high samples showed "a high rate of significantly mutated genes in important immune modulating pathways and antigen presentation machinery," Dr. Grasso and colleagues added.
The researchers were able to identify 11 mutated immune-related genes that were involved in modulating hematopoietic cell types and had effects beyond antigen presentation, "suggesting potential novel therapeutic targets."
"Most MSI-high cases had at least one mutation thought to play a role in decreasing antigen presentation. Also, these and other findings indicate that immune editing is happening before treatment and patient tumors are on a resistance continuum that needs to be monitored in advance of treatment, "the team noted.
Co-author Dr. Antoni Ribas noted, "We have evidence that colon cancer is being attacked by the immune system from the start, even before immunotherapies based on immune checkpoint blockade have been given to patients."
Colorectal cancers have genetic events associated with activated WNT signaling and T-cell exclusion. The researchers note, "it should be possible to monitor better resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not occur."
"This large-scale study shows the means by which a highly immunogenic tumor type, MSI-High colorectal cancer, outwits the immune system," said Dr. Charles Swanton, University College London, who was not involved in the research.