IL-17 producing mast cells promote the expansion of myeloid-derived suppressor cells in a mouse allergy model of colorectal cancer
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Xiaowei Chen1,2,3, Michael J. Churchill2, Karan K. Nagar1,2, Yagnesh H. Tailor1,2, Timothy Chu1,2, Brittany S. Rush2, Zhengyu Jiang1,2, Edwin B.C. Wang1,2, Bernhard W. Renz1,2, Hongshan Wang1,2, Ming Chiu Fung3, Daniel L. Worthley1,2, Siddhartha Mukherjee2, Timothy C. Wang1,2
1Division of Digestive and Liver Disease, Columbia University, New York, NY, USA
2Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
3Division of Biology, School of Life Science, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China
Timothy C. Wang, e-mail: [email protected]
Keywords: histamine deficiency, mast cell, IL-17, myeloid-derived suppressor cell, colorectal cancer
Received: July 17, 2015 Accepted: September 15, 2015 Published: September 26, 2015
Food allergy can influence the development of colorectal cancer, although the underlying mechanisms are unclear. While mast cells (MC) store and secrete histamine, immature myeloid cells (IMC) are the major site of histidine decarboxylase (HDC) expression, the enzyme responsible for histamine production. From our earlier work, we hypothesized that histamine is central to the association between allergy and colorectal carcinogenesis through its influence on the MC-MDSC axis. Here, we show that in wild type (WT) mice, ovalbumin (OVA) immunization elicits a typical TH2 response. In contrast, in HDC−/− mice, the response to OVA allergy is skewed towards infiltration by IL-17 expressing MCs. This response is inhibited by histamine treatment. The HDC−/− allergic IL-17-expressing MCs promote MDSC proliferation and upregulation of Cox-2 and Arg-1. OVA allergy in HDC−/− mice increases the growth of colon tumor cells in both the MC38 tumor cell implantation model and the AOM/DSS carcinogenesis model. Taken together, our results show that histamine represses IL-17-expressing MCs and their subsequent activation of MDSCs, attenuating the risk of colorectal cancer in the setting of food allergy. Targeting the MC-MDSC axis may be useful for cancer prevention and treatment in patients, particularly in those with food allergy.
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