Nav: Home

Precancerous colon polyps in patients with Lynch syndrome exhibit immune activation

April 16, 2018

HOUSTON - Colon polyps from patients with Lynch syndrome, a hereditary condition that raises colorectal cancer risk, display immune system activation well before cancer development, according to research from The University of Texas MD Anderson Cancer Center. The preclinical research challenges traditional models of cancer immune activation and suggests immunotherapy may be useful for colorectal cancer prevention in certain high-risk groups.

The findings, published in JAMA Oncology, will be presented today at the American Association for Cancer Research Annual Meeting 2018 in Chicago by Kyle Chang, graduate research assistant.

Immune checkpoint inhibitors targeting PD-1, such as pembrolizumab and nivolumab, have been successful in treating colorectal cancers with deficiencies in DNA mismatch repair (MMR). These tumors accumulate large numbers of genetic mutations and mutant proteins, or neoantigens, which are thought to stimulate an immune response, making them more susceptible to checkpoint blockade therapy.

"Our question was how this worked in premalignancy," said senior author Eduardo Vilar-Sanchez, M.D., Ph.D., assistant professor of Clinical Cancer Prevention and Gastrointestinal (GI) Medical Oncology. "Can we apply checkpoint inhibitors or checkpoint inhibitor strategies to prevent MMR-deficient colorectal cancer?"

Lynch syndrome (LS), which is caused by inherited mutations in MMR, provides the perfect context in which to study early immune activation and explore the potential use of checkpoint inhibitors in a prevention setting, explained Vilar-Sanchez. Over 1 million people in the U.S. are affected by LS, the most common hereditary colorectal cancer syndrome.

In the study, the researchers analyzed gene expression to characterize the immune profile in 11 polyps and three early-stage tumors from 14 patients with LS. As a control, the researchers also analyzed 17 polyps from patients with Familial Adenomatous Polyposis (FAP), a hereditary colorectal cancer syndrome which does not exhibit MMR deficiencies.

The resulting profiles revealed increased expression of several markers of immune activation, including CD4 T-cells, proinflammatory molecules and checkpoint molecules, such as PD-L1 and LAG-3, in LS polyps compared to FAP polyps. However, contrary to traditional models of immune activation, the observed immune profiles were independent of the rate of mutations or neoantigens present in the sample.

"To our surprise, our findings don't follow the standard model. The majority of premalignant lesions do not have an excessive increase in mutations or neoantigens," said Vilar-Sanchez. "However, we observed there is already immune activation, meaning the activation precedes the development of the mutations."

The findings suggest a baseline level of immune activation exists in precancerous polyps, which may prime them for susceptibility to checkpoint blockade, explained Vilar-Sanchez.

Future work will be necessary to clarify the mechanism by which this immune activation occurs, as the current study was observational in nature. The researchers hope to initiate clinical studies to investigate the use of checkpoint blockade strategies for preventing colorectal cancer in high-risk groups, such as those with LS.

"Lynch syndrome patients have a strong immune activation in the colon, and that immune activation can be exploited for preventive purposes," said Vilar-Sanchez. "I think our data provide the information needed to launch studies to use checkpoint inhibition in the setting of prevention."
This study was supported, in part, by the Colorectal Cancer Moon Shot™, part of MD Anderson's Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives. The Moon Shot provides valuable funding support for high-risk, high-reward projects, such as this, and propels research toward delivering clinical impact, said Vilar-Sanchez.

This work also was supported by the National Cancer Institute (R21 CA208461, R01 CA219463, R25T CA057730, P30 CA016672, K12 CA088084), a gift from the Feinberg Foundation, and The V Foundation For Cancer Research Scholar Grant.

In addition to Vilar-Sanchez, MD Anderson authors include: Kyle Chang, Laura Reyes-Uribe, M.D., Ester Borras, Ph.D., Erick Riquelme, Ph.D., Reagan Barnett, Ph.D., and Ernest Hawk, M.D., all of Clinical Cancer Prevention; Melissa Taggart, M.D., Pathology; F. Anthony San Lucas, Ph.D., Epidemiology; Nancy You, M.D., Surgical Oncology; Jason Roszik, Ph.D., Melanoma Medical Oncology and Genomic Medicine; Paul Scheet, Ph.D., Epidemiology; Scott Kopetz, M.D., Ph.D., GI Medical Oncology; Patrick Lynch, M.D., J.D, Gastroenterology; and Florencia McAllister, M.D., Clinical Cancer Prevention and GI Medical Oncology. Additional authors include: Guido Leoni, Ph.D., and Maria Catanese, Ph.D., Nouscom SRL, Rome; Federica Mori, ReiThera SRL, Rome; Maria G. Diodoro, M.D., Regina Elena National Cancer Institute, Rome; and Alfred Nicosia, Ph.D., of Nouscom SRL, Rome, CEINGE and University of Naple Federico II, Naples, Italy.

University of Texas M. D. Anderson Cancer Center

Related Lynch Syndrome Articles:

Increasing the age limit for Lynch syndrome genetic testing may save lives
Raising the age limit for routine genetic testing in colorectal cancer could identify more cases of families affected by Lynch syndrome, a condition that accounts for around 5 percent of all colon cancers.
Avocados may help combat the metabolic syndrome
A new review investigates the effects of avocados on different components of metabolic syndrome, which is a clustering of risk factors including high blood sugar, cholesterol, blood pressure, and body mass index.
What does congenital Zika syndrome look like?
In a new paper, researchers at University of California San Diego School of Medicine, along with colleagues in Brazil and Spain, describe the phenotypic spectrum or set of observable characteristics of congenital Zika (ZIKV) syndrome, based upon clinical evaluations and neuroimaging of 83 Brazilian children with presumed or confirmed ZIKV congenital infections.
A new immunologic and endocrine syndrome
The name of the gene is Armc5, for Armadillo repeat containing 5.
Double effort against Rett's syndrome
Although our genes normally come in pairs but sometimes one of them is missing (haploinsufficiency) leading sometimes to serious diseases.
New neurodevelopmental syndrome identified
Columbia University researchers discovered a new neurodevelopmental syndrome and the genetic mutation that causes it.
New drug target for Rett syndrome
Harvard Stem Cell Institute researchers have identified a faulty signaling pathway that, when corrected, in mice ameliorates the symptoms of Rett syndrome, a devastating neurological condition.
Insensitive irritable bowel syndrome
For the first time, biopsies of patients with irritable bowel syndrome have shown that the nerves in their gut wall respond poorly to a cocktail of inflammatory substances.
MECP2 duplication syndrome is reversible
Research led by Huda Zoghbi, M.D., at Baylor College of Medicine and HHMI and published today in the journal Nature reveals that the MECP2 Duplication Syndrome is reversible.
AGA recommends all patients with colorectal cancer get tested for Lynch syndrome
All colorectal cancer patients should undergo tumor testing to see if they carry Lynch syndrome, the most common inherited cause of colorectal cancer, according to a new guideline was published in Gastroenterology, the official journal of the American Gastroenterological Association.

Related Lynch Syndrome Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Don't Fear Math
Why do many of us hate, even fear math? Why are we convinced we're bad at it? This hour, TED speakers explore the myths we tell ourselves and how changing our approach can unlock the beauty of math. Guests include budgeting specialist Phylecia Jones, mathematician and educator Dan Finkel, math teacher Eddie Woo, educator Masha Gershman, and radio personality and eternal math nerd Adam Spencer.
Now Playing: Science for the People

#518 With Genetic Knowledge Comes the Need for Counselling
This week we delve into genetic testing - for yourself and your future children. We speak with Jane Tiller, lawyer and genetic counsellor, about genetic tests that are available to the public, and what to do with the results of these tests. And we talk with Noam Shomron, associate professor at the Sackler School of Medicine at Tel Aviv University, about technological advancements his lab has made in the genetic testing of fetuses.