Interferon-γ and celecoxib inhibit lung-tumor growth through modulating M2/M1 macrophage ratio in the tumor microenvironment

Abstract

Tumor-associated macrophages play an important role in tumor growth and progression. These macrophages are heterogeneous with diverse functions, eg, M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth. In this study, we found that IFNγ and/or celecoxib (cyclooxygenase-2 inhibitor) treatment consistently inhibited tumor growth in a mouse lung cancer model. IFNγ alone and celecoxib alone increased the percentage of M1 macrophages but decreased the percentage of M2 macrophages in the tumors, and thus the M2/M1 macrophage ratio was reduced to 1.1 and 1.7 by IFNγ alone and celecoxib alone, respectively, compared to the M2/M1 macrophage ratio of 4.4 in the control group. A combination of IFNγ and celecoxib treatment reduced the M2/M1 macrophage ratio to 0.8. Furthermore, IFNγ and/or celecoxib treatment decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, as well as the density of microvessels in the tumors, compared to the control group. This study provides the proof of principle that IFNγ and/or celecoxib treatment may inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio in the tumor microenvironment, suggesting that IFNγ and celecoxib have potential to be further optimized into a new anticancer therapy.

Keywords:

• tumor-associated macrophages
• M1 macrophages
• M2 macrophages
• lung cancer
• interferon-γ
• celecoxib

Acknowledgments

This work was partially supported by the National Natural Science Foundation of China (NSFC 81172236 – The mechanism of TAMs activation in lung cancer and a novel immunotherapy; NSFC 81372505 – The role of IL-17 in formation and progression of primary lung cancer and the underlying molecular mechanisms) and the Key Science and Technology Program of Sichuan Province, People’s Republic of China (2009SZ0152 and 2011SZ0111) to LL. ZY was partially supported by two grants from the National Institute of General Medical Sciences (P20GM103518) and the National Cancer Institute (R01CA174714) of the National Institutes of Health, three grants from Department of Defense Health Program through the Prostate Cancer Research Program (W81XWH-14-1-0050, W81XWH-14-1-0149, and PC130118; the US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office), the Developmental Fund of Tulane Cancer Center (TCC), and Louisiana Cancer Research Consortium (LCRC) Fund. The content of this article is solely the responsibility of the authors, and does not necessarily represent the official views of the National Institutes of Health or the Department of Defense.

Disclosure

The authors report no conflicts of interest in this work.