April 20, 2018
Immune helper cells appear to fuel pancreatic cancer development
BY Scott Merville
Immune cells that rush to repair damage caused by inflammatory tissue are subverted to cancer-promoting allies by pancreas cells that feature the most common cancer-driving mutation for the disease, researchers from MD Anderson Cancer Center report online in the journal Gastroenterology.
“Chronic inflammation is a risk factor for pancreatic cancer, but the underlying mechanisms of that connection have been unknown,” says Florencia McAllister, M.D., assistant professor of Clinical Cancer Prevention at MD Anderson and senior author of the paper.
“We’ve shown that in the context of pancreas cells with mutated KRAS, T helper 17 (TH17) cells normally involved in regeneration don’t help heal, they instead convert damaged cells into cancer stem cells that promote rapid cancer development,” McAllister says.
KRAS mutations, which promote out-of-control cell growth, occur in 95% of pancreatic cancers.
TH17 cells secrete interleukin 17 (IL17), a pro-inflammatory cytokine. McAlister and colleagues showed in an earlier paper that blocking IL17 in the context of KRAS-mutated cells prevented initiation of cancer. The present research outlines IL17’s cancer-promoting mechanism.
Pancreatitis – chronic inflammation of the pancreas – has been a known risk factor for pancreatic cancer, and other risk factors such as smoking, obesity and the onset of diabetes also are associated with inflammation and the presence of IL17.
Working in cancer cell lines and mouse models that develop precancerous growths called PanINs (pancreatic intraepithelial neoplasia), the team found that IL17 exposure caused expression of genes associated with embryonic stem cells rather than with normal outer tissue (epithelium) of the pancreas. Their expression accelerated tumor development in mice with PanINs.
Reduced survival for patients
Previous research has shown that human pancreatic cancer includes stem cells that contribute to relapse and resistance to chemotherapy.
McAllister, lead author Yu Zhang, Ph.D., and colleagues found that IL17 increased the expression of DCLK1, POU2F3 and ALDH1A1, reprogramming epithelial cells to stem cells. The team discovered that this gene expression was reversed when IL17 was blocked with antibodies or treated with helper T cells that don’t express IL17.
Expression of two of those stemness genes, doublecortin like kinase 1 (DCLK1) and POU class 2 homebox3 (POU2F3), also characterizes tuft cells – chemosensory cells that have been recently described as pancreatic tumor-initiating cells, McAllister says.
Analysis of 65 surgically removed human pancreatic cancer tumors showed that patients with high levels of DCLK1 had a shorter median survival time, 17.7 months, compared to 26.6 months for those with low levels. A separate analysis of 170 patients from the Cancer Genome Atlas database showed expression of POU2F3 and another stemness gene, LAMC2, indicate a poor prognosis.
The team found that IL17 directly regulates DCLK1 by activating the NFkB pathway, a vital protein complex that controls gene activation, cytokine production and cell survival.
“Disrupting this pathway between IL17 and stem-cell programming could help us prevent pancreatic tumor growth and progression,” McAllister says.
Commercially available antibodies to block IL17 could play a role, the team notes.
The American Cancer Society estimates 55,000 people will develop pancreatic cancer in 2018, and an estimated 44,000 will die from the disease. Only 7% of patients survive to five years.
McAllister’s lab is working to further understand the role of the IL17-induced stemness signature genes in pancreatic cancer development and to dissect the role of IL17 signaling in advanced cancer.
Research was funded by the PanCAN/AACR Career Development Award, the National Pancreas Foundation, the V Foundation, and a grant from the National Cancer Institute (K12CA088084-16A1).