HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

Clin Cancer Res. 2016 Aug 15;22(16):4119-32. doi: 10.1158/1078-0432.CCR-15-2584. Epub 2016 Mar 10.


Purpose: A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ∼20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response.

Experimental design: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms.

Results: We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells.

Conclusions: These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119-32. ©2016 AACR.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / immunology*
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Animals
  • Biomarkers
  • Cell Line, Tumor
  • Chemokines / genetics*
  • Disease Models, Animal
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Immunotherapy
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Models, Biological
  • Molecular Targeted Therapy
  • Mutation
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / physiology*
  • Treatment Outcome
  • Tumor Burden


  • Biomarkers
  • Chemokines
  • Histone Deacetylase Inhibitors
  • Programmed Cell Death 1 Receptor