Immunoediting processes help colorectal cancer escape immune attack

Last Updated: 2018-03-22

By David Douglas

NEW YORK (Reuters Health) - Frequent immunoediting helps microsatellite-instability-high (MSI-high) colorectal cancer evade the immune system, according to a new genomic analysis.

In a report online March 6 in Cancer Discovery, researchers note that, "it has been observed previously that MSI-high or immune-infiltrated tumors have evolved mutations that may confer resistance to recognition by the immune system in untreated samples (i.e. immunoediting)."

"Here," write Dr. Catherine S. Grasso of the University of California, Los Angeles, and colleagues, "we demonstrate that there are other factors besides mutation load affecting T-cell infiltration in both MSI-high and MSS. Specifically, we show that MSI-high tumors frequently undergo 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."

Added Dr. Grasso in an email to Reuters Health: "The cancer and the immune system are at an impasse, but the cancer evolves to develop resistance to the immune system by knocking out how it is recognized."

The new work is 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 in the antigen presentation machinery," Dr. Grasso and colleagues write.

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. Moreover, these and other findings "indicate that immune editing is happening prior to treatment and that patient tumors are on a resistance continuum that needs to be monitored in advance of treatment," the team writes.

As co-author Dr. Antoni Ribas, also of UCLA, told Reuters Health by email, "We now 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 and methylation events associated with activated WNT signaling and T-cell exclusion. Thus, the researchers observe, "it should be possible to better monitor 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."

"This large-scale study shows the means by which a highly immunogenic tumour type, MSI-High colorectal cancer, outwits the immune system," said Dr. Charles Swanton, a professor of personalized cancer medicine at University College London, who was not involved in the research.

"In a typical evolutionary tug of war between predator (immune system) and prey (the cancer), the cancer evolves mechanisms to evade immune attack by deleting immune recognition molecules that present mutated peptides to the immune system and by activating oncogenic pathways that deplete the tumour microenvironment of T cells," he told Reuters Health by email.

SOURCE: http://bit.ly/2GfiWYQ

Cancer Discov 2018.