Wnt signaling on a colon cancer tissue (positive staining for nuclear CTNNB1) is inversely correlated with immune infiltration (CD3, CD8, CD45RO, but not FOXP3 staining). Image: Courtesy of Dr. Jonathan Nowak
A UCLA-led study has found how colon cancer alters its genes during development to avoid detection by the immune system, creating a specific genetic imprint in the process. This ability of cancer to change its genes — a process called immunoediting — had never been described in colon cancer before; the new understanding could help researchers to develop new immunotherapies that target those genetic changes.
“By identifying the evolution of changes needed to escape the immune system, researchers should be able to design treatments that empower the immune system to outsmart the cancer,” says Catherine Grasso, PhD, assistant professor of medicine at the David Geffen School of Medicine at UCLA. “We expect that in the future, we’ll be testing new immunotherapies to prevent the development of colon cancer, while also using combinations of different agents to treat advanced cancers.”
Investigators from UCLA’s Jonsson Comprehensive Cancer Center, the Broad Institute, the Parker Institute for Cancer Immunotherapy and the Fred Hutchinson Cancer Institute used the genetic analyses of more than 1,200 colon cancers from the Cancer Genome Atlas, the Nurses’ Health Study and the Health Professionals Follow-up Study. Because the cancers were sequenced at the DNA and RNA levels, researchers were able to make highly detailed assessments of the changes that were made to evade the immune system.
Among their findings was that more mutated cancers, called MSI-high (for high microsatellite instability), have more alterations of genes that interact with the immune system. That is significant because the 15 percent of colon cancers in this category currently can be treated with a type of immunotherapy that acts on a specific receptor, known as PD-1, located on cells in the immune system. This receptor normally functions as a brake to the immune system.
Immunotherapy releases this brake, allowing the immune system to attack cancer cells when it recognizes their high frequency of mutations as abnormal. Knowing how cancer cells change could help scientists further refine immunotherapy treatments for such cancers.
The study also shed light on the 85 percent of colon cancers that are not MSI-high. These cancers have fewer mutations and are not usually attacked by the immune system; instead, they have alterations in Wnt signaling, a pathway important in cell development. The study documents the extent to which Wnt-activating mutations were associated with the lack of an immune response in the tumor.
“The genetic data show that colon cancer is being attacked by the immune system from the start, even before immunotherapies based on an immune-checkpoint blockade have been given to patients,” says Antoni Ribas, MD (FEL ’98, ’01), director of the cancer center’s Tumor Immunology Program.
Researchers also showed that as Wnt signaling increases, immune infiltration in colon cancer decreases. This suggested that inhibitors of Wnt signaling could potentially stimulate immune infiltration so that the tumors could respond to immunotherapy.
“Genetic Mechanisms of Immune Evasion in Colorectal Cancer,” Cancer Discovery, March 6, 2018.
