Low-dose SAHA enhances CD8+T cell-mediated antitumor immunity by upregulating MHC I expression in non-small cell lung cancers

Abstract

Non-small cell lung cancers (NSCLCs) is a highly aggressive lung cancer with poor responses to traditional therapies like surgery, radiotherapy, and chemotherapy. While immunotherapy has become an effective approach treating multiple types of cancer, solid tumors frequently exhibit immune escape through various mechanisms, including downregulation of MHC I expression. Whether upregulating MHC I expression can improve the immunotherapeutic effect for NSCLCs remains unexplored. Suberoylanilide hydroxamic acid (SAHA) is a potent histone deacetylase (HDAC) inhibitor, which has been applied clinically to treat lymphoma, but high-dose of SAHA kills tumor cells and normal cells without preference. Here, we show that low-dose SAHA enhances CD8 + T cell-mediated antitumor immunity via upregulating MHC I expression in NSCLC cells. We also provide evidence that high levels of MHC I induced by SAHA promoted the activation, proliferation, and cytotoxicity of specific CD8+T cells in mouse models. Mechanistically, low-dose SAHA increases the levels of H3K9ac and H3K27ac in the promoters of STAT1, Smad2 and Smad3 genes in NSCLC cells by inhibiting HDAC activity, resulting in elevated expression levels of STAT1, Smad2 and Smad3. The nuclear translocation of phosphorylated STAT1 and Smad2/3 upregulates the expression of MHC I in NSCLC cells remarkably. Thus, we uncovered a key mechanism of SAHA-mediated enhanced antitumor immunity, providing insights into a novel immunotherapy strategy for NSCLC.