Researchers at the University of Colorado Cancer Center have published exciting findings in the Proceedings of the National Academy of Sciences reporting on NLRP3. NLRP3 is an intracellular complex that has been found to participate in melanoma-mediated inflammation, which can result in tumor growth and progression. The paper describes how inhibition of NLRP3 was shown to decrease inflammation and tumor growth.
"NLRP3 is a member of a larger family that is involved in sensing danger signals," explains Carlo Marchetti, PhD from CU Cancer Center. "It is a receptor that surveils the intercellular compartment of a 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 into its biologically active form, causing an intense inflammatory response. We found that in melanoma, this process is dysregulated, resulting in tumor growth."
As Marchetti explains, interleukin-1-beta is a cytokine that generally triggers inflammation as part of the normal immune response to infection. Yet, with melanoma, the inflammation can go haywire and actually result in tumor growth and metastasis.
"Checkpoint inhibitors increase the efficacy of the immune system to kill tumors, but sometimes tumors become resistant to this treatment," Marchetti says. "A big part of cancer research now is to find therapies that can be combined with checkpoint inhibitors to improve their efficacy."
The researchers tested the impact of a known NLRP3 inhibitor called Dapansutrile and found that not only does it enhance the immune response, it can also decrease the side effects of other checkpoint inhibitors. This will have real significance to melanoma patients, says the team, especially for those who don't respond to checkpoint inhibitors alone.
"This was a very collaborative project that involved a lot of members of the university, and we are very excited about it," concludes Marchetti. “This project is important because it further shows that NLRP3-mediated inflammation plays a critical role in the progression of melanoma, and it opens new strategies to improve patient care."