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Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression

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Abstract

The role and characteristics of tumor-associated neutrophils (TAN) in cancer are poorly defined. We have recently shown that TAN can have anti-tumorigenic (N1) or pro-tumorigenic (N2) functions. An interesting unanswered question is how the phenotype of TAN is influenced by the ongoing evolvement of tumor microenvironment. We therefore studied the phenotype and effects of TAN at different time points during tumor progression. We used two models of murine tumor cancer cell lines—Lewis lung carcinoma (LLC) and AB12 (mesothelioma). Neutrophils were studied at early and late stages and compared to each other and to neutrophils from bone marrow/periphery of naïve mice. Although there was no difference in the number of neutrophils entering the tumor, we found that at early stages of tumor development, neutrophils were almost exclusively at the periphery of the tumor. Only at later stages, neutrophils were also found scattered among the tumor cells. We further found that TAN from early tumors are more cytotoxic toward tumor cells and produce higher levels of TNF-α, NO and H2O2. In established tumors, these functions are down-regulated and TAN acquire a more pro-tumorigenic phenotype. In line with this phenotype, only depletion of neutrophils at later stages of tumor development inhibited tumor growth, possibly due to their central location in the tumor. Our work adds another important layer to the understanding of neutrophils in cancer by further characterizing the changes in TAN during time. Additional research on the functional role of TAN and differences between subsets of TAN is currently underway.

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Acknowledgments

This study was supported by a Research Career Development Award from the Israel Cancer Research Fund, and partly by The Israel Cancer Association (Grant 20110103-B) and by the joint research fund of the Hebrew University and Hadassah Medical Center (Jerusalem, Israel).

Conflict of interest

There are no financial or other interests that might be construed as conflict of interest.

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Authors and Affiliations

  1. Laboratory of Lung Cancer Research, Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel

    Inbal Mishalian, Rachel Bayuh, Liran Levy, Lida Zolotarov, Janna Michaeli & Zvi Gregorio Fridlender

  2. Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA

    Zvi Gregorio Fridlender

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  1. Inbal Mishalian
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  2. Rachel Bayuh
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Correspondence to Zvi Gregorio Fridlender.

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Mishalian, I., Bayuh, R., Levy, L. et al. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol Immunother 62, 1745–1756 (2013). https://doi.org/10.1007/s00262-013-1476-9

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