title: Using macrophage activation to augment immunotherapy of established tumours.
abstract: BACKGROUND
  Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy.
  
  
  METHODS
  We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT-PCR).
  
  
  RESULTS
  In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8(+) T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect.
  
  
  CONCLUSIONS
  Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials.
authors.affiliation: Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel. fridlender@hadassah.org.il
authors.forename: Z G
authors.initials: ZG
authors.lastname: Fridlender
authors.forename: A
authors.initials: A
authors.lastname: Jassar
authors.forename: I
authors.initials: I
authors.lastname: Mishalian
authors.forename: L-Cs
authors.initials: LC
authors.lastname: Wang
authors.forename: V
authors.initials: V
authors.lastname: Kapoor
authors.forename: G
authors.initials: G
authors.lastname: Cheng
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.forename: S
authors.initials: S
authors.lastname: Singhal
authors.forename: L
authors.initials: L
authors.lastname: Levy
authors.forename: S M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*; D044004:Xanthones / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan