Infiltration of Alternatively Activated Macrophages in Cancer Tissue Is Associated with MDSC and Th2 Polarization in Patients with Esophageal Cancer

PLOS ONE, Aug 2014

Myeloid derived suppressor cells (MDSCs) expand in cancer bearing hosts and contribute to tumor immune evasion. M2 macrophages constitute a major cellular component of cancer-related inflammation. However, the correlation between circulating MDSCs and infiltrating M2 macrophages in tumor tissues from patients with esophageal cancer (ECA), and its potential relationship with the polarization of Th2 cells remain unclear. In the present study, we showed the level of MDSCs in PBMC and Arg1 in plasma were significantly elevated in ECA patients, and the increased ratio of MDSC in PBMC was closely related to the expression of CD163 in cancer tissues. In addition, the ECA patients exhibited remarkable increases in the mRNA levels of IL-4 and GATA3, as well as the protein levels of IL-13 and IL-6, but IFN-γ and IL-12 in peripheral blood were decreased. Our data indicate that the increased Th2 cytokines are associated with MDSCs and M2 macrophages polarization, and foster the infiltration of CD163+M2 macrophages in cancer tissues, which promote the formation of immunosuppressive microenvironment in ECA patients.

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Infiltration of Alternatively Activated Macrophages in Cancer Tissue Is Associated with MDSC and Th2 Polarization in Patients with Esophageal Cancer

et al. (2014) Infiltration of Alternatively Activated Macrophages in Cancer Tissue Is Associated with MDSC and Th2 Polarization in Patients with Esophageal Cancer. PLoS ONE 9(8): e104453. doi:10.1371/journal.pone.0104453 Infiltration of Alternatively Activated Macrophages in Cancer Tissue Is Associated with MDSC and Th2 Polarization in Patients with Esophageal Cancer Jingjing Gao 0 Yumin Wu 0 Zhaoliang Su 0 Prince Amoah Barnie 0 Zhijun Jiao 0 Qingli Bie 0 Liwei Lu 0 Shengjun Wang 0 Huaxi Xu 0 Jacques Zimmer, Centre de Recherche Public de la Sante (CRP-Sante), Luxembourg 0 1 Department of Immunology, School of Medical Science and Laboratory Medicine, Jiangsu University , Zhenjiang , P. R. China , 2 Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University , Zhenjiang , P. R. China , 3 Department of Laboratory Medicine, Suzhou Hospital Affiliated to Nanjing Medical University , Suzhou , P. R. China , 4 Department of Pathology and Centre of Infection and Immunology, The University of Hong Kong , Hong Kong , P. R. China Myeloid derived suppressor cells (MDSCs) expand in cancer bearing hosts and contribute to tumor immune evasion. M2 macrophages constitute a major cellular component of cancer-related inflammation. However, the correlation between circulating MDSCs and infiltrating M2 macrophages in tumor tissues from patients with esophageal cancer (ECA), and its potential relationship with the polarization of Th2 cells remain unclear. In the present study, we showed the level of MDSCs in PBMC and Arg1 in plasma were significantly elevated in ECA patients, and the increased ratio of MDSC in PBMC was closely related to the expression of CD163 in cancer tissues. In addition, the ECA patients exhibited remarkable increases in the mRNA levels of IL-4 and GATA3, as well as the protein levels of IL-13 and IL-6, but IFN-c and IL-12 in peripheral blood were decreased. Our data indicate that the increased Th2 cytokines are associated with MDSCs and M2 macrophages polarization, and foster the infiltration of CD163+M2 macrophages in cancer tissues, which promote the formation of immunosuppressive microenvironment in ECA patients. - Funding: This work was supported by grants from the National Natural Science Foundation of China (31270947, 31170849 and 30972748, http://www.nsfc.gov. cn/), Natural Science Foundation of Jiangsu Province (BK2011472) and the Postdoctoral Foundation of China (2012M511705). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. " These authors are co-first authors on this work. Esophageal cancer (ECA) is one of the most common malignancies all over the world and the fourth leading cancer death in China [13]. There are increasing evidences of the crucial role of the immune system in malignant tumors, but the precise mechanisms of immune modulation in ECA patients remain elusive. In the past decade, the role of the immunosuppressive and cancer-promoting myelomonocytic compartment within the tumor environment has also received a great deal of attention [4]. Although mechanisms are incompletely understood, cancer promotes the accumulation of a heterogeneous pool of bone marrow-derived immature, poorly differentiated myelomonocytic cells (monocytes, neutrophils, immature macrophages and dendritic cells), called myeloid derived suppressor cells (MDSCs), which are major host component contributing to the immunosuppressive environment. In pathological conditions, a partial block in the differentiation of immature myeloid cells into matured myeloid cells results in an expansion of MDSCs [5]. Recently, it has become clear that the suppressive activity of MDSCs requires various factors which promote their expansion or induce their activation. These factors, which include IL-4, IL-13, ligands for Toll-like receptors (TLRs), and transforming growth factor-b (TGF-b), activate several different signalling pathways in MDSCs that involve STAT6 and nuclear factor-kB (NF-kB). Similar to MDSCs, macrophages are a diverse population of myeloid cells which undergo specific differentiation depending on the stimulating agents, as documented extensively. Recent immunological studies have identified two distinct states of the polarized macrophage activation: the classically activated (or M1) and the alternatively activated (or M2) macrophage phenotypes. M1 macrophages are typically activated by IFN-c and LPS, whereas M2 macrophages are activated by IL-4 and IL-13 [6]. M1 macrophages are tumoricidal and promote tumor rejection, whereas M2 macrophages promote tumor progression [79]. Both M2 macrophages and MDSCs are a major source of immunosuppression that allows tumor-escape from effective anticancer responses, but no information on the relationship between M2 macrophages and MDSCs in the development of esophageal cancer is currently available. A (...truncated)


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Jingjing Gao, Yumin Wu, Zhaoliang Su, Prince Amoah Barnie, Zhijun Jiao, Qingli Bie, Liwei Lu, Shengjun Wang, Huaxi Xu. Infiltration of Alternatively Activated Macrophages in Cancer Tissue Is Associated with MDSC and Th2 Polarization in Patients with Esophageal Cancer, PLOS ONE, 2014, Volume 9, Issue 8, DOI: 10.1371/journal.pone.0104453