Deregulation of innate lymphoid cells leads to progression of colon cancer and resistance to immunotherapy

A subset of immune cells called innate lymphoid cells (ILC3) protect against colorectal cancer, in part by helping to maintain a healthy dialogue between the immune system and gut microbes, according to a new study by researchers at Weill Cornell Medicine and NewYork-Presbyterian. This discovery opens the door to new strategies to treat this type of cancer.

The researchers, who published their results Aug. 17 in Cell, showed that ILC3s tend to be significantly reduced and functionally altered in people with colorectal cancer. In addition, they demonstrate that experimental disruption of ILC3 functions in mice leads to aggressive colon cancer and dramatically reduces the efficacy of anti-cancer immunotherapies.

Colorectal cancer is the fourth most common cancer in the United States, with approximately 150,000 new cases each year and approximately 50,000 deaths. While the early detection of these precancerous cancers or polyps with screening colonoscopies is very effective, treatments for advanced colorectal tumors remain a major challenge with limited treatment options. Oncologists are particularly concerned about the relative resistance of these tumors to immunotherapies, treatments that work well against certain other cancers by boosting the immune system’s ability to attack malignant cells.

“These findings suggest new possibilities for the clinical approach to colorectal cancer and also help explain why this type of cancer often does not respond to immunotherapies,” said lead author Dr Gregory Sonnenberg, associate professor of microbiology and of Immunology in Medicine in the Division of Gastroenterology and Hepatology and Fellow of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.

One factor impacting resistance to immunotherapies may be the gut microbiome, the population of bacteria and other microbial species that reside in the intestines and normally aid digestion, support various metabolic functions, and play a role in regulating the system. immune. Colorectal cancer is associated with chronic intestinal inflammation and major disruption of the normal microbiome. Additionally, recent studies suggest that patient microbiomes play a key role in controlling the outcome of cancer immunotherapies and may explain why some patients’ cancers respond or not respond well to treatment.

In the new study, Dr Sonnenberg and colleagues, whose lead author Dr Jeremy Goc, an associate researcher in Dr Sonnenberg’s lab, examined the role of ILC3s, which reside in the intestines and are known to help mediate the relationship between immune system microbes and intestine.

Innate group 3 lymphoid cells normally play a key role in maintaining a healthy dialogue between the microbiome and the immune environment in the lower intestine. In close collaboration with Dr Manish Shah, Bartlett Family Professor of Gastrointestinal Oncology, Director of the Gastrointestinal Oncology Program in the Division of Hematology and Medical Oncology, and member of the Sandra and Edward Meyer Cancer Center of Weill Cornell Medicine, the research group analyzed colorectal tumors and precancerous polyps in humans and mice. They found that ILC3s in cancerous tissue were relatively depleted compared to healthy tissue and were still fundamentally impaired in their functions.

This is an exciting discovery that could have broad implications for our understanding of the pathways that control the pathogenesis, progression, and therapeutic responsiveness of gastrointestinal malignancies. “

Dr Manish Shah, study co-author, head of the Solid Tumor Oncology Service and co-director of the Center for Advanced Digestive Care at NewYork-Presbyterian / Weill Cornell Medical Center

Among this loss of normal ILC3 activity in the intestine, the authors further observed that the ability of ILC3s to regulate a specific subset of immune cells called T cells was significantly disrupted. This disruption of the dialogue between ILC3s and T cells further led to increased inflammation in the gut which subsequently alters the gut microbiome. These changes in the gut microbes in turn induce a decrease in the levels of T cells which are effective in fighting tumors.

These collective results have major consequences for tumor development, the researchers have shown. In mice that develop colon cancers, blocking ILC3 signaling led to the growth of abnormally invasive and more aggressive tumors with poor results. And when colon tumors were implanted in mice with blocked ILC3 signaling, the tumors were relatively unresponsive to an anti-cancer immunotherapy called anti-PD-1 checkpoint blockade, whereas the same type of tumor, implanted in mice with normal ILC3 signaling responded well to therapy.

Finally, in colorectal tissue biopsied from patients with inflammatory bowel disease (IBD), researchers found ILC3-related abnormalities similar to those of patients with colorectal cancer. Transplantation of microbes from IBD patients to mice conferred resistance to treatment, while mice transplanted with microbes from healthy human donors always responded well to blocking anti-PD-1 checkpoints.

“A better understanding of the contribution of the microbiome to cancer development and responsiveness to treatment could revolutionize patient management strategies. This study sheds light on a mechanism of therapeutic resistance driven by microbiome deregulation that has not been appreciated so far, ”said Dr Goc. “This suggests, for example, that one day we could sample the gut microbiota to predict tumor progression and responsiveness to immunotherapy, and even use healthy microbiota to improve responsiveness to treatment.”

Researchers are now working to identify the most beneficial species of gut bacteria in this regard. This research is supported in part by a new funding mechanism from the Cancer Research Institute which was awarded to Dr. Sonnenberg in 2019, the inaugural year of the program.