Potential Role for Vaccines, Checkpoint Inhibitors in Chemoprevention of Lynch Syndrome

Next-generation sequencing of colorectal polyps associated with Lynch Syndrome (LS) showed a distinct immune profile and antigen repertoire that may allow for use of vaccines or immune checkpoint inhibitors as cancer prevention methods in mismatch repair (MMR)-deficient premalignant lesions, according to results of a study published in JAMA Oncology.

“We have shown that LS polyps exhibit a unique immune profile with upregulation of checkpoints that is independent of mutational rates and neoantigen formation, suggesting that the development of an immune environment is present in early steps of MMR-deficient carcinogenesis,” wrote Kyle Chang, BSc, of The University of Texas MD Anderson Cancer Center, and colleagues. “These findings have an important implication in the development of immunotherapies as checkpoint inhibitors and vaccines for cancer prevention in patients with LS.”

LS occurs due to the presence of germline mutations in one of the DNA MMR genes. Therefore, LS is an attractive model to study carcinogensis in DNA MMR deficiency, which accounts for about 15% of sporadic colorectal cancer.

This study was designed to characterize the immune profile or colorectal polyps in patients with LS. To do that, Chang and colleagues performed whole-genome next-generation sequencing in colorectal polyps and carcinoma of a small group of patients with LS. These were compared with samples taken from patients with familial adenomatous polyposis (FAP) and 47 colorectal carcinomas taken from The Cancer Genome Atlas.

Analysis was completed on 28 polyps and 3 early-stage LS colorectal tumors taken from 24 patients, 14 with LS and 10 with FAP. The patients with LS had low mutational and neoantigen rates, but had striking immune activation profiles characterized by CD4 T cells, proinflammatory and checkpoint molecules, and PD-L1.

“Among the immune checkpoints upregulated in polyps stands LAG3, which constitutes a promising target for immune interception in this patient population,” the researchers wrote. “Therefore, the emergence of high mutation burdens and neoantigens cannot simply be applied as a biomarker to guide implementation and development of immunoprevention strategies.”

The immune profile identified was independent of mutation rate, neoantigen formation, and MMR status.

“We believe that the results of this study open the field of immunoprevention in LS to checkpoint inhibitors as an immune interception strategy,” the researchers wrote. “This class of agents have shown a high level of clinical activity in the treatment of stage IV MMR-deficient CRC. Although toxicity has to be carefully considered in the setting of prevention in healthy carriers and cancer survivors, it is ubiquitously accepted that cancer risks associated with LS outweigh potential toxic effects cataloged to date.”