Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis

Abstract Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat BRAFV600E/K-mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal.…

• UD
  U.S. Department of Defense

  Award: PC150650
• AC
  American Cancer Society

  Award: PF-18-096-01-LIB
• TJ
  Thomas Jefferson University

  Award: P30 CA056036
• DR
  Dr. Ralph and Marian Falk Medical Research Trust
• P
  Plexxikon
• NI
  National Institutes of Health

  Awards: CA196278, P30 CA056036, CA182635, R01 CA196278, AR074564, R01 CA182635, CA207855, CA160495, R01 CA160495, AR055398
• NC
  National Cancer Institute

  Awards: CA207855, CA196278, CA182635, CA160495