Cancer immunotherapy methods turn up the heat on cancer. Some methods effectively strip cancer cells of their immune-system-deceiving disguises. Other methods subject cancer cells to the targeted killing that is meted out by engineered T cells. And now a new cancer immunotherapy method is being developed, one that is positively inflammatory. That is, it promotes a highly inflammatory form of cell death called pyroptosis. How? By reactivating a gene for gasdermin E.
Gasdermin E appears to encode a protein that suppresses tumors. The problem, however, is that the gene is often mutated or silenced in many cancers. With hopes of rekindling gasdermin E’s antitumor activity, scientists based at Boston Children’s Hospital induced ectopic expression of gasdermin E in mouse models of cancer. The scientists not only demonstrated that this intervention could inhibit tumor growth, they also learned that gasdermin E suppresses tumors by converting apoptosis, a relatively subdued form of cell death, to fiery pyroptosis.
Detailed findings appeared March 11 in the journal Nature, in an article titled, “Gasdermin E suppresses tumor growth by activating anti-tumor immunity.” According to this article, GSDME in tumors suppresses tumor growth by increasing the number and antitumor functions of tumor-infiltrating natural-killer (NK) and CD8+ T killer lymphocytes. It also enhances the phagocytosis of tumor cells by tumor-associated macrophages.
“Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function,” the article’s authors wrote. “In mice, knocking out Gsdme in GSDME-expressing tumors enhances, whereas ectopic expression in Gsdme-repressed tumors inhibits, tumor growth.”
The scientists, led by Judy Lieberman, MD, PhD, chair, cellular and molecular medicine at Boston Children’s Hospital and professor, pediatrics at Harvard Medical School, showed that in live mice, pyroptosis sounds a potent immune alarm that recruits killer T cells to suppress the tumor. When they reintroduced gasdermin E to mouse models where gasdermin E had been lacking, they were able to trigger pyroptosis and suppress growth of a variety of tumors (triple-negative breast tumors, colorectal tumors, and melanoma).
“Gasdermin E is a very potent tumor suppressor gene, but in most tumor tissues, it’s either not expressed or it’s mutated,” explained Lieberman. “When you reactivate gasdermin E in a tumor, it can convert an immunologically ‘cold’ tumor—not recognized by the immune system—into a ‘hot’ tumor that the immune system can control.”
Lieberman and colleagues are now investigating therapeutic strategies for inducing gasdermin E to rally that antitumor immune response.
“What we’re suggesting is that if we can turn on the danger signal, which is inflammation, we can activate lymphocytes more fully than with other immunotherapy approaches, and have immunity that is potentially much broader,” she noted. “Combining activation of inflammation in the tumor with approved checkpoint inhibitor drugs could work better than either strategy on its own.”
Checkpoint inhibitors are drugs that help the immune system recognize cancer cells as foreign. These drugs, however, work for just a minority of cancer types. The same could be said of another cancer immunotherapy method, chimeric antigen receptor (CAR) T-cell therapy. Also, CAR T-cell therapy carries significant risks. The limitations of checkpoint inhibitors and CAR T cells could be addressed by therapeutic strategies that incorporate pyroptosis.
“We have shown here that many cancer-related GSDME mutations reduce pyroptosis, and that mutations of D270, the shared GzmB/caspase 3 cleavage site and a prominent cancer mutation, have enabled tumors to evade tumor suppression by GSDME,” the authors of the Nature article concluded. “Therapeutic strategies to induce GSDME—such as use of the DNA methylation inhibitor decitabine, an approved leukemia and myelodysplasia drug—are worth exploring.”