ABSTRACT
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.
Subject(s)
CTLA-4 Antigen/genetics , CTLA-4 Antigen/immunology , Epigenesis, Genetic , Germ-Line Mutation , Neoplasms/genetics , Neoplasms/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Autophagy , Cell Line, Tumor , DNA Methylation , Female , Gene Expression Profiling , Humans , Immunotherapy , Ipilimumab/pharmacology , Male , Melanoma/genetics , Melanoma/immunology , Melanoma-Specific Antigens/genetics , Melanoma-Specific Antigens/immunology , Mice , Mice, Transgenic , Skin Neoplasms/genetics , Skin Neoplasms/immunologyABSTRACT
SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.