Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

Abstract

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development. Regardless, it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses, thus allowing continuous tumor growth and development. Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer. Compared with other cancers, pancreatic cancer has a tumor microenvironment that can resist most treatment modalities, including emerging immunotherapy. Sadly, the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients, suggesting that pancreatic cancer has successfully evaded immunomodulation. In this review, we summarize the impact of genetic alteration and epigenetic modification (especially histone deacetylases, HDAC) on immune evasion in pancreatic cancer. HDAC overexpression significantly suppresses tumor suppressor genes, contributing to tumor growth and progression. We review the evidence on HDAC inhibitors in tumor eradication, improving T cells activation, restoring tumor immunogenicity, and modulating programmed death 1 interaction. We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

Keywords: Histone acetylation; Histone deacetylases inhibitors; Immune evasion; Pancreatic cancers; Pancreatic ductal adenocarcinoma.