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Expert Critique

FROM THE ASCO Reading Room

Vinay Gupta, MD Hematology/Oncology Willamette Valley Cancer Institute

Immunotherapy for GI malignancies with microsatellite instability (MSI-high) has been proven to be effective and is in clinical practice. This article discussed immune dysregulation in pre-malignant states, as in colonic polyps, and whether the immune profile of these pre-cancerous lesions could be a target for preventive strategies using checkpoint inhibition. Researchers employed next-generation sequencing (NGS) to analyze the immune profile of polyps from patients with Lynch syndrome and from patients with familial adenomatous polyposis (FAP). Interestingly, precancerous polyps were noted to have an activated immune profile and theoretically could be amenable to inhibition by checkpoint inhibitors. A vaccination strategy in these patients is also plausible, particularly in Lynch syndrome and FAP.

Full Critique

Precancerous colon polyps exhibit immune activation, opening up an opportunity for immunotherapy to prevent certain colon cancers, researchers say.

Immune checkpoint inhibitors targeting programmed death-1 (PD-1), such as pembrolizumab and nivolumab, have been successful in (MMR). These tumors accumulate large numbers of genetic mutations and neoantigens, which are thought to stimulate an immune response, making them more susceptible to checkpoint blockade therapy.

"We know tumors in MMR and Lynch syndrome because they accumulate many mutations. This triggers an immune response of abnormal regulation of PD-1 markers, and is the reason why programmed death-ligand 1 [PD-L1] inhibitors are an effective treatment," Eduardo Vilar-Sanchez, MD, PhD, of the Department of Clinical Cancer Prevention at the University of Texas MD Anderson Cancer Center in Houston, told 名媛直播.

Immune dysregulation also exists in premalignancy, his group found, in a study online in . "This breaks from the existing model in which we thought neoantigens activate the immune profile. Immune activation is already present in precancerous lesions with no increase in mutations."

Other factors may also contribute to conditioning immune activation, including the presence of certain neoantigens or possibly the microbiome, explained Vilar-Sanchez, who is also director of the Department of Human and Molecular Genetics at the University of Texas Graduate School of Biomedical Sciences.

No one knows how pre-malignancy or cancer forms in Lynch syndrome, he added. "There is not a lot of literature about what happens in earlier stages. Lynch syndrome is the perfect syndrome to inform us about how this particular subgroup of colorectal cancer evolves." Lynch syndrome carcinomas are infiltrated by abundant tumor-infiltrating lymphocytes.

This hypermutated colorectal cancer makes up 15% of all colorectal cancers. More than one million people in the United States are affected by Lynch syndrome, the most common hereditary colorectal cancer syndrome.

The researchers set out to see whether they could apply checkpoint inhibitors or checkpoint inhibitor strategies to prevent MMR-deficient colorectal cancer. The team analyzed gene expression to characterize the immune profile in 11 polyps and three early-stage tumors from 14 patients with Lynch syndrome. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection.

For controls, the researchers also analyzed 17 polyps from patients with familial adenomatous polyposis (FAP), a hereditary colorectal cancer syndrome that does not exhibit MMR deficiencies. In addition, a total of 47 colorectal carcinomas (six hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas for comparisons.

The whole-genome transcriptomic analysis using next-generation sequencing was performed in a total of 28 polyps (26 tubular adenomas and two hyperplastic polyps) and three early-stage Lynch syndrome colorectal tumors from 24 patients, mean age of 48, who were diagnosed with FAP (10 patients) or Lynch syndrome (14 patients).

Lynch syndrome polyps presented with low mutational and neoantigen rates, but displayed a striking immune activation profile characterized by CD4 T cells, pro-inflammatory factors (tumor necrosis factor, interleukin 12) and checkpoint molecules, including lymphocyte activation gene 3 (LAG3) and PD-L1, the researchers found. This immune profile was independent of mutational rate, neoantigen formation, and MMR status.

In addition, the team identified a small subset of Lynch syndrome polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed an additional checkpoint, cytotoxic T-lymphocyte–associated protein 4 (CTLA4), and neoantigens involved in DNA damage response (ATM and BRCA1 signaling).

Contrary to traditional models of immune activation, all polyps analyzed presented a consistent immune profile regardless of the mutation rate or abundance of high-affinity binding neoantigens. Immune deregulation could precede the accumulation of genomic aberrations and neoantigen formation in the initial steps of carcinogenesis, Vilar-Sanchez said.

The findings suggest that a baseline level of immune activation exists in precancerous polyps, which may prime them for susceptibility to checkpoint blockade. Future work, he said, will be necessary to clarify the mechanism by which this immune activation occurs. The plan is to initiate clinical studies to investigate the use of checkpoint blockade strategies for preventing colorectal cancer in high-risk groups, such as those with Lynch syndrome.

"Lynch syndrome patients have a strong immune activation in the colon, and that immune activation can be exploited for preventive purposes. We have a proven activation target of several checkpoint inhibitors. We should be able to use this target as prevention. Now we need to find biomarkers to explore where to apply checkpoint inhibitors."

The next step in the research will be to better define the catalog of neoantigens that are activated and trigger the immune response. "We can also apply select antigens to combine for vaccine development to prevent the progression of carcinogenesis by priming T cells to antigens displayed by early lesions that will be cleared at the premalignant stage. And immune activation at premalignant stages opens the door to better deploy checkpoint inhibitors as potential prevention strategies."

Combinations of vaccine approaches and single or dual-checkpoint blockade are logical next steps in the development of immunoprevention in this hereditary disease, he noted.