Colorectal cancers may mutate to escape immune system detection in many ways

October 30, 2017, American Association for Cancer Research

Whole exome sequencing revealed that colorectal cancers with high mutational load (MSI-H) predominantly use "immunoediting" to escape immune surveillance while colorectal cancers with low mutational load (MSS) use oncogenic signaling to escape from the immune response, according to data presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 26-30. The data suggest that promoting immune-cell infiltration into MSS colorectal tumors by blocking certain cancer genes could potentially make them respond to immunotherapies.

"Immunoediting is the evolution of mutations in the tumor to knock out the immune system before treatment because there is selection pressure in place between the T cells and the tumor," explained Catherine Grasso, PhD, assistant professor in the Department of Hematology and Oncology at University of California, Los Angeles. "The tumor and the immune system are at an impasse, but the tumor evolves to develop resistance to the immune system by knocking out surveillance."

It is important to study colorectal tumors prior to treatment to assess whether the tumor is being attacked by the immune system, because immunotherapies based on immune checkpoint blockade will not work if the tumor is not being attacked, explained Grasso. The researchers sought to identify novel immunotherapeutic opportunities in colorectal by comparing cancers from the subtypes that respond to immunotherapy and those that do not respond.

Grasso and colleagues used colorectal tumor exome data from 592 cases from The Cancer Genome Atlas (TCGA), and 619 cases from the Nurses' Health Study and the Health Professionals Follow-up Study to examine immunoediting in MSI-H (179 cases) and MSS (1,032 cases) tumors. They used the MutSigCV algorithm and identified highly mutated that are unique for MSI-H (40 genes) and MSS (nine genes) tumors, and those that were present in both types of tumors (13 genes).

The researchers found that mutations in some genes that were specific for MSI-high were novel, involved in modulating the immune system and the antigen presenting machinery. "There are many ways for the immune system to fail in recognizing and attacking a cancer cell due to mutations in the tumor cells and we found examples of them," noted Grasso. Some of the immune pathways that the tumors evade, through gene mutations, were those involving trafficking of the immune cells around the body, infiltration of immune cells, antigen presentation, signaling between the tumor and the T cells, and signaling methods of the T to kill the .

"For MSI-H colorectal cancers, these mutation data suggest the need for targeted sequencing to monitor immune competence before anti-PD1 treatment, which will ensure that people do not get treatments to which they may not respond," Grasso said.

"Our data suggest that mutation load is not the sole predictor of infiltration, which has been reported frequently in the literature," she added. For example, Grasso and colleagues showed that WNT signaling correlated negatively with immune infiltration in colorectal cancer, like melanoma. This suggested that inhibitors of WNT signaling could potentially stimulate immune infiltration, so that the tumors could respond to anti-PD1 therapy. This is important because it indicates that tumors with low mutational load, such as MSS , may be stimulated to be attacked by prior to anti-PD1 treatment, Grasso noted.

A limitation of the study is that the researchers only looked at the genetic and molecular predictors of T-cell infiltration and did not study the responses to immune checkpoint blockade, because response data was not available. "We have just scratched the surface of what is possible in immunotherapy. Funding for large genomics studies will continue to provide deep insights," Grasso said, "especially as we accrue and study samples before and after treatment."

Explore further: Gut microbes may promote immune responses against colorectal cancer

Related Stories

Gut microbes may promote immune responses against colorectal cancer

September 6, 2017
Bacteria in the gut could stimulate tumor cells to produce factors that regulate cell mobility called chemokines that recruit T cells to the tumor, which is linked to improved outcomes, according to data presented at the ...

Genetic alteration allowing lung cancers to escape the immune system may occur late in tumor evolution

October 27, 2017
A specific genetic alteration that could allow cancer cells to escape the immune system was detected in 40 percent of non–small cell lung cancers (NSCLCs) analyzed, according to data presented at the AACR-NCI-EORTC International ...

Molecular fingerprint of breast tumors linked to immune response in bloodstream

September 28, 2017
Using newly developed software, researchers have shown that genes and molecular processes in breast cancer tumor cells are tightly linked to genes and processes in blood cells, including immune system cells. The findings ...

Researchers identify key mutation that suppresses the immune system in melanoma

March 7, 2017
University of California, Irvine researchers have identified a specific mutation that allows melanoma tumor cells to remain undetected by the immune system. The finding may lead to the development of better immunotherapies ...

Number of mutations in a tumor varies by age and type of cancer

May 17, 2017
A team of investigators led by researchers at Georgetown Lombardi Comprehensive Cancer Center has found that the tumor mutation load, or TML, in a patient's cancer biopsy varied by age and the type of cancer, along with several ...

Adding immunotherapy to RFA may benefit colorectal cancer patients with liver metastasis

March 1, 2016
Radiofrequency ablation (RFA), a procedure to treat liver metastases in patients with colorectal cancer, was found to induce antitumor immune responses in human samples of primary colon tumor, and mice treated with a combination ...

Recommended for you

Discovery of kidney cancer driver could lead to new treatment strategy

July 19, 2018
University of North Carolina Lineberger Comprehensive Cancer Center scientists have uncovered a potential therapeutic target for kidney cancers that have a common genetic change. Scientists have known this genetic change ...

High fruit and vegetable consumption may reduce risk of breast cancer, especially aggressive tumors

July 19, 2018
Women who eat a high amount of fruits and vegetables each day may have a lower risk of breast cancer, especially of aggressive tumors, than those who eat fewer fruits and vegetables, according to a new study led by researchers ...

Sunscreen reduces melanoma risk by 40 per cent in young people

July 19, 2018
A world-first study led by University of Sydney has found that Australians aged 18-40 years who were regular users of sunscreen in childhood reduced their risk of developing melanoma by 40 percent, compared to those who rarely ...

Analysis of prostate tumors reveals clues to cancer's aggressiveness

July 19, 2018
Using genetic sequencing, scientists have revealed the complete DNA makeup of more than 100 aggressive prostate tumors, pinpointing important genetic errors these deadly tumors have in common. The study lays the foundation ...

Complementary medicine for cancer can decrease survival

July 19, 2018
People who received complementary therapy for curable cancers were more likely to refuse at least one component of their conventional cancer treatment, and were more likely to die as a result, according to researchers from ...

Overcoming resistance to a standard chemotherapy drug

July 19, 2018
Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works. Researchers at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.