Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion
Isak W. Tengesdal, Dinoop Ravindran Menon, Douglas G. Osborne, C. Preston Neff, Nicholas E. Powers, Fabia Gamboni, Adolfo G Mauro, Angelo D’Alessandro, Davide Stefanoni, Morkos A. Henen, Taylor Mills, Dennis M. de Graaf, Tania Azam, Beat Vögeli, Brent E. Palmer, Eric M. Pietras, James DeGregori, Aik Choon Tan, Leo A. B. Joosten, Mayumi Fujita, Charles A. Dinarello, Carlo Marchetti
Abstract
T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.