title: HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Weipeng
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Cihui
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida. Department of Cancer Biology PhD Program, University of South Florida, Tampa, Florida.
authors.forename: Crystina C
authors.initials: CC
authors.lastname: Watson
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Massengill
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida. Department of Cancer Biology PhD Program, University of South Florida, Tampa, Florida.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Chris
authors.initials: C
authors.lastname: Massengill
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: David R
authors.initials: DR
authors.lastname: Noyes
authors.affiliation: Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Martinez
authors.affiliation: Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Roha
authors.initials: R
authors.lastname: Afzal
authors.affiliation: Department of Bioinformatics, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida. Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Antonia
authors.affiliation: Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida. Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Brian
authors.initials: B
authors.lastname: Ruffell
authors.affiliation: Department of Immunology, Moffitt Cancer Center, Tampa, Florida. Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida. amer.beg@moffitt.org.
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics*; D004195:Disease Models, Animal; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000502:physiology*; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D015415:Biomarkers; D018925:Chemokines; D056572:Histone Deacetylase Inhibitors; D061026:Programmed Cell Death 1 Receptor