Colorectal polyps from patients with Lynch syndrome, a hereditary condition that increases colorectal cancer risk, display immune system activation well before cancer development, according to preclinical research from The University of Texas MD Anderson Cancer Center. This finding challenges traditional models of cancer immune activation and suggests that immunotherapy may be useful for colorectal cancer prevention in such patients.
Lynch syndrome, the most common hereditary colorectal cancer syndrome, is caused by inherited mutations in DNA mismatch repair (MMR) genes. Colorectal cancers with MMR deficiencies accumulate large numbers of mutant proteins called neoantigens, which are believed to stimulate an immune response. And such cancers can be successfully treated with immune checkpoint inhibitors. However, not much was known about immune activation in premalignant colorectal polyps in patients with Lynch syndrome.
Therefore, researchers led by Eduardo Vilar-Sanchez, M.D., Ph.D., an assistant professor in the Departments of Clinical Cancer Prevention and Gastrointestinal Medical Oncology, analyzed gene expression to characterize the immune profile in 11 premalignant polyps and three early-stage tumors from 14 patients with Lynch syndrome. As a control, the researchers analyzed 17 premalignant polyps from patients with familial adenomatous polyposis (FAP), a hereditary colorectal cancer syndrome that does not exhibit MMR deficiencies.
The resulting profiles revealed significantly higher expression of several markers for immune activation—including CD4-positive T cells, proinflammatory molecules, and checkpoint proteins such as PD-L1 and LAG3—in Lynch syndrome polyps than in FAP polyps. However, contrary to traditional models of immune activation, the immune profiles in the Lynch syndrome polyps were independent of the rate of mutations or neoantigens.
“Our findings don’t follow the standard model. The majority of premalignant lesions do not have an excessive increase in mutations or neoantigens,” Dr. Vilar-Sanchez said. “However, there is already immune activation, meaning the activation precedes the development of the mutations.”
In April 2018, Dr. Vilar-Sanchez and colleagues published the study’s report online in JAMA Oncology (doi: 10.1001/jamaoncol.2018.1482), and graduate research assistant Kyle Chang presented the findings at the American Association for Cancer Research Annual Meeting (session No. PO.PR01.02).
The researchers hope to initiate clinical studies of immunotherapy to prevent colorectal cancer in high-risk populations such as patients with Lynch syndrome.
OncoLog, May-June 2018, Volume 63, Issue 5-6