Cancer Research Institute to Honor Scientists for Groundbreaking Discoveries Leading to New Immune-Based Strategies that Target Gasdermins in Cancer Treatment

The Cancer Research Institute (CRI), a nonprofit organization dedicated to harnessing the immune system’s power to control and potentially cure all types of cancer, will confer its prestigious 2022 William B. Coley Award for Distinguished Research in Basic and Tumor Immunology on four scientists for their collective work that revealed the role of the pore-forming gasdermins in pyroptosis and promotion of anti-tumor immunity, setting the stage for targeting gasdermins in cancer therapeutics.

Judy Lieberman, MD, PhD, and Hao Wu, PhD, of Boston Children’s Hospital and Harvard Medical School, Feng Shao, PhD, of the National Institute of Biological Sciences, Beijing, and Vishva Dixit, MD, of Genentech will receive their Coley Awards during an evening ceremony taking place Tuesday, September 27, at The New York Hilton Midtown, where CRI with its partners the European Network for Cancer Immunotherapy (ENCI) and the American Association for Cancer Research (AACR) will host their four-day International Cancer Immunotherapy Conference.

Gasdermins (GSDMs) are a family of proteins originally identified and named from their expression in the gastrointestinal tract and the skin. In 2015, Dixit and Shao’s groups discovered that gasdermin D (GSDMD) is a substrate of inflammatory caspases, which are activated downstream of the immune system’s inflammasomes when they sense pathogen- or damage-associated molecules. GSDMD is the key executioner of inflammasome-induced inflammatory cell death called pyroptosis in immune sentinel cells and is responsible for the secretion of IL-1 family cytokines. Pyroptosis is a highly immunogenic form of cell death, and pyroptosis in cancer in theory could result in the release of danger-associated molecules and neoantigens to alert the immune system and promote antitumor immunity.

In 2016, Lieberman and Wu, and Shao, went on to demonstrate the mechanisms by which gasdermins effect cell death. Specifically, they discovered that upon processing by inflammatory caspases, the GSDMD N-terminal domain (GSDMD-NT) binds acidic lipids and forms cell membrane pores that are responsible for cell death. These pores also release mature IL-1 family cytokines and other danger signals, including chemokines, which recruit and activate immune cells to the site of danger. The requirement for binding to acidic lipids for GSDMD pore formation and the enrichment of these lipids in the inner leaflet of the cytoplasmic membrane suggested that GSDMD kills from within the cell but does not harm bystander mammalian cells. Lieberman and Wu further showed that GSDMD kills bacteria upon activation by binding to an acidic lipid called cardiolipin on bacterial membranes. Shao developed a crystal structure of a GSDM family member, mouse GSDMA3, showing that GSDMD-NT is autoinhibited by the GSDMD C-terminal region in full-length GSDMD. Dixit and other groups subsequently published their identification of the pore-forming activity of GSDMD.

“Discovery of the pore-forming activity of GSDM proteins changed the definition of pyroptosis from a ‘fiery death’ induced by inflammasome activation to GSDM-mediated lytic cell death, opening the search for other proteolytic pathways for activating GSDMD and other GSDMs,” says Frederick W. Alt, PhD, a Howard Hughes Medical Institute Investigator and director of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital and a member of the CRI Scientific Advisory Council.

The direct relationship to cancer of another gasdermin, GSDME, became clear in a series of papers authored by Lieberman and Wu, and Shao. They showed that the expression of GSDME is often repressed or mutated to lose its function in cancers while expression of GSDME converts noninflammatory apoptosis to inflammatory pyroptosis, effectively altering immunogenically “cold” tumors that do not ignite an anticancer immune response into “hot” tumors that attract killer cytotoxic T lymphocytes and natural killer cells. Shao showed that delivery of gasdermins via cancer-targeting nanoparticles can result in cancer cell pyroptosis in mice, resulting in the suppression of entire tumor grafts, not only the targeted tumor tissue because the treatment activated an effective adaptive immune response to the tumor.

“The groundbreaking molecular and mechanistic studies carried out by Lieberman and Wu, Shao, and Dixit along with the preclinical development of effective therapeutics that can convert immunologically cold tumors to hot have made possible therapeutic interventions that specifically activate GSDMs in cancer cells to promote antitumor immunity and responsiveness to checkpoint blockade immunotherapy,” said Jill O’Donnell-Tormey, PhD, CEO and director of scientific affairs at the Cancer Research Institute.

In addition to presenting the 2022 William B. Coley Award, the ceremony will also feature the presentation of the 2022 Frederick W. Alt Award for New Discoveries in Immunology to David Masopust, PhD, the McKnight University Professor and a Howard Hughes Medical Institute Faculty Scholar in the Department of Microbiology and Immunology at the University of Minnesota, for his body of research focused on T cell development and biology, primarily memory T cell development and behavior. The Alt Award is given to a former CRI postdoctoral fellow whose work has made a significant impact on the fields of immunology or tumor immunology. Masopust received CRI funding while carrying out postdoctoral research in the laboratory of renowned immunologist and virologist Rafi Ahmed, PhD, at Emory University, from 2002-2005.

Event Contact
Lynne Harmer, +1-212-688-7515 x226, [email protected]

Media Contact
Brian M. Brewer, +1-212.688.7515 x242, [email protected]

About the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology
The Cancer Research Institute established this award in 1975 in honor of Dr. William B. Coley, now regarded as the Father of Cancer Immunotherapy, whose daughter Helen Coley Nauts (1907-2001) founded the Cancer Research Institute. Considered CRI’s highest scientific accolade as well as a predictor of more widely recognized scientific honors including the Lasker Award and Nobel Prize, the Coley Award has been given to 119 immunologists and tumor immunologists including the 2022 recipients. 

About Cancer Research Institute
The Cancer Research Institute (CRI), founded in 1953, is a highly rated U.S. nonprofit organization dedicated exclusively to saving more lives by fueling the discovery and development of powerful immunotherapies for all cancers. Guided by a world-renowned Scientific Advisory Council that includes four Nobel laureates and 27 members of the National Academy of Sciences, CRI has invested $500 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment. To learn more, go to cancerresearch.org.