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. Importantly, BRAFi + MEKi–resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi–induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-0672
Entities
People
- Adam C. Berger
- Andrew E Aplin
- Conroy O. Field
- Corey Rogers
- Dan A. Erkes
- Edward J. Hartsough
- Emad S. Alnemri
- Ileine M. Sanchez
- Timothy J Purwin
- Ulrich Rodeck
- Weijia Cai
Organizations
- American Cancer Society
- Dr. Ralph and Marian Falk Medical Research Trust
- Drexel University
- National Cancer Institute
- National Institutes of Health
- Thomas Jefferson University
- United States Department of Defense