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.

CONCLUSION:

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: Z G Fridlender, A Jassar, I Mishalian, L-Cs Wang, V Kapoor, G Cheng, J Sun, S Singhal, L Levy, S M Albelda
• Journal: British journal of cancer (Br J Cancer) Vol. 108 Issue 6 Pg. 1288-97 (Apr 02 2013) ISSN: 1532-1827 [Electronic] England
• PMID: 23481183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Xanthones
• vadimezan

Topics

• Adenocarcinoma, Bronchiolo-Alveolar (immunology, pathology, therapy)
• Animals
• Antineoplastic Agents (therapeutic use)
• CD8-Positive T-Lymphocytes (immunology)
• Carcinoma, Lewis Lung (immunology, pathology, therapy)
• Combined Modality Therapy
• Female
• Immunotherapy
• Lung Neoplasms (immunology, pathology, therapy)
• Macrophage Activation (drug effects)
• Macrophages (drug effects, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Myeloid Cells (cytology, immunology)
• Neutrophils (cytology, immunology)
• Tumor Microenvironment (immunology)
• Xanthones (therapeutic use)