Tumor Cell–Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer

Recently, in a study published in Cancer Research, scientists from New York University and other institutions have found that a key immune signal may play a previously unknown role in turning off the immune system to attack pancreatic cancer. The researchers found that the immune signaling protein interleukin 1β (IL-1β) can be made and released by pancreatic tumor cells, while it reduces the body's anti-cancer immune response, thereby promoting the growth of pancreatic ductal adenocarcinoma (PDA), a type of cancer that is usually fatal within two years.

The researchers say blocking IL-1 Beta activity in mice with antibodies may reduce PDA tumor growth by 32%, while other experiments can combine anti-IL-1β antibodies (which can lock and neutralize their targets) with antibody therapies that have been approved to turn off the PD1 protein checkpoint. To protect normal cells from immune attack, the immune system uses checkpoints on immune cells to turn off when they receive normal signals; cancer cells intercept checkpoints to turn off the function of the immune system, triggering the immune knowledge of CD8 + T cells, which in turn kills cancer cells, a therapy called checkpoint inhibitors can effectively neutralize this effect.

Although effective against a variety of cancers, checkpoint inhibitors are helpless for the treatment of PDA. In some experiments, the tumor response rate to therapy is only about 3%, and poor CD8 + T cell infiltration and immunosuppression are the main reasons for the limitations. In the current study, the researchers found that adding anti-IL-1β antibody to anti-PD-1 antibody therapy doubled T cell infiltration into PDA and increased the anti-tumor activity of PD-1 blockers by 40%.

Dr. Dafna Bar-Sagi, a researcher, said that by engineering mice to lack the IL-1β gene, we found for the first time that pancreatic cancer cells can produce IL-1β, which is essential for the continued growth of PDA tumors, and blocking IL-1β using antibody therapy may provide a novel strategy to make pancreatic tumors on the host immune system, thus potentially increasing the therapeutic potential of checkpoint inhibitors.

The findings of this study are consistent with previous research work by other researchers, which describe that the body's microbiome changes when PDA is present, and that the microbiome is a key factor in cancer growth, an area that traditionally allocates IL-1β production to immune cells, but this study found that pancreatic tumor cells can also respond to proteins released by specific bacteria. The researchers say bacterial products can activate a protein on the cell surface called toll-like receptors, which can turn on the chain reaction needed for IL-1β production in cancer cells.

In addition, the researchers found that high levels of IL-1β promoted increased production of high-density proteins such as collagen in nearby pancreatic stellate cells, an overgrowth of fibrous tissue that often occurs near pancreatic tumors and is not associated with treatment resistance. Active pancreatic stellate cells are able to induce the production of signaling proteins, which can attract macrophages into tumors and reprogram them to become M2 macrophages that can effectively inhibit immune responses; now researchers have confirmed that high levels of IL-1β and M2 macrophages and fibroblast-driven connective tissue formation may reduce the ability of CD8 + T cells that kill cancer cells to enter tumors.

Finally, researcher Shipra Das said, this study provides strong evidence that blocking IL-1β activity may promote better penetration of T cells into tumors and kill cancer cells, which may hopefully overcome the dilemmas and limitations of current immunotherapy in the treatment of pancreatic cancer.