Inhibition of the NLRP3 complex may reduce inflammation in patients with melanoma

Cancer doctors will soon be able to get a new tool to treat melanoma and other cancers, thanks to the work of researchers from the Cancer Center at the University of Colorado.

In a paper published in a journal PNAS last month, members of the CU Mayumi Fujita Cancer Center, dr. med., dr. Angelo D’Alessandro, Ph.D. sc. Morkos Henen, Ph.D. sc. Beat Vogeli, dr. Eric Pietras, Ph.D. James DeGregori, Ph.D. Carlo Marchetti and Charles Dinarello, dr. Med., Along with Isaac Tengesdale, MS, a graduate student in the Department of Infectious Diseases at the University of Colorado School of Medicine, describe in detail their work on NLRP3, an intracellular complex found to be involved in melanoma-mediated inflammation leading to tumor growth and progression.

By inhibiting NLRP3, the researchers found, they can reduce inflammation and the resulting spread of the tumor.

In particular, NLRP3 promotes inflammation by inducing the maturation and release of interleukin-1-beta, a cytokine that causes inflammation as part of the normal immune response to infection. However, in cancer, inflammation can cause the tumor to grow and spread.

NLRP3 is a member of a larger family involved in recognizing danger signals. It is a receptor that monitors the intercellular part of the cell, looking for dangerous molecules or pathogens. When NLRP3 recognizes these signals, it leads to the activation of caspase-1, a protein involved in the processing and maturation of interleukin-1-beta to its biologically active form, causing an intense inflammatory response. We found that in melanoma this process is disordered, resulting in tumor growth. “

Dr. Carlo Marchetti, University of Colorado

The oral NLRP3 inhibitor used in their study (dapansutril) has already been shown to be effective in clinical trials for the treatment of gout and heart disease, and is currently being tested on COVID-19. CU cancer researchers are now trying to find out if this NLRP3 inhibitor can be used successfully in patients with melanoma who are resistant to checkpoint inhibitors.

“Checkpoint inhibitors increase the efficiency of the immune system to kill tumors, but sometimes tumors become resistant to this treatment,” says Marchetti. “A big part of cancer research now is finding therapies that can be combined with checkpoint inhibitors to improve their effectiveness.”

Assuming that the NLRP3 inhibitor is one of these therapies, researchers at the CU Cancer Center are studying the drug’s effects on melanoma, as well as breast cancer and pancreatic cancer. In addition to improving the immune response, an NLRP3 inhibitor may also help reduce the side effects of checkpoint inhibitors. Marchetti says this research could make a big difference for melanoma patients who do not respond on their own to checkpoint inhibitors.

“This was a very collaborative project that involved a lot of university members and we are very excited about that,” he says. This project is important because it further demonstrates that NLRP3-mediated inflammation plays a crucial role in the progression of melanoma and opens up new strategies to improve patient care. “

Source:

University of Colorado Anschutz Medical Campus

Journal reference:

Tengesdal, IW, and others. (2021) Targeting tumor-derived NLRP3 reduces melanoma progression by limiting the spread of MDSC. PNAS. doi.org/10.1073/pnas.2000915118.

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