Leveraging GSDMD-Mediated Pyroptosis as a Therapy for Melanoma 

Melanoma is the most lethal skin cancer, leading to an estimated 8,290 deaths and 100,640 new cases in 2024. Melanoma was traditionally very difficult to treat, which has changed in the past 15 years with the onset of immunotherapies. Despite their success, many patients do not respond to immunotherapy and are in need of secondary treatments. Different forms of cell death are able to improve the recognition of tumors by the immune system. A form of cell death called pyroptosis is when proteins in the cells, gasdermins, poke holes on the cell surface, causing various cellular components to leak out and stimulate the immune system. Pyroptosis improves immunotherapy in several cancers, thus we wondered if a particular form of pyroptosis driven by gasdermin D might improve the success of immunotherapy in melanoma. 

In the first aim of our project, we propose to study if causing pyroptosis through gasdermin D is able to effect tumor growth in cutaneous melanoma like model system. We will test if the immune system is needed for any tumor growth effects we observe after causing pyroptosis. Next, we will dissect the specific immune responses caused by gasdermin D driven pyroptosis, specifically testing the reliance of these immune responses on a specific population of immune stimulatory cells. Lastly, we will determine if specific factors released from pyroptotic cancer cells are driving the immune responses and tumor growth effects we observe. We ultimately expect to find that pyroptosis through gasdermin D slows tumor growth by engaging the immune system. 

For the second aim of this grant, we propose testing if pyroptosis induction through gasdermin D can improve the effect of immunotherapy in cutaneous melanoma tumor models. Specifically, we will investigate the best timing of pyroptosis induction to improve immunotherapy and lead to immune responses that can impact distant tumors that model metastases. We will also work with The Wistar Institute to screen thousands of anti-cancer drugs to discover which can cause pyroptosis through gasdermin D. We will then test to see if the drugs identified can slow the growth of primary and metastatic tumors through so called abscopal effects. With this aim we expect to leverage pyroptosis to improve immunotherapy in melanoma and discovery new treatments for melanoma.