Effects of immune cells and cytokines on inflammation and immunosuppression in the tumor microenvironment

Dmitrieva, 2016, Interleukins 1 and 6 as main mediators of inflammation and cancer, Biochemistry (Moscow), 81, 80, 10.1134/S0006297916020024 Grivennikov, 2010, Immunity, inflammation, and cancer, Cell, 140, 883, 10.1016/j.cell.2010.01.025 Dvorak, 1986, Tumors: wounds that do not heal, N. Engl. J. Med., 315, 1650, 10.1056/NEJM198612253152606 Coussens, 2002, Inflammation and cancer, Nature, 420, 860, 10.1038/nature01322 Hanahan, 2000, The hallmarks of cancer, Cell, 100, 57, 10.1016/S0092-8674(00)81683-9 Hanahan, 2011, Hallmarks of cancer: the next generation, Cell, 144, 646, 10.1016/j.cell.2011.02.013 Brown, 2002, Tumor microenvironment and the response to anticancer therapy, Cancer Biol. Ther., 1, 453, 10.4161/cbt.1.5.157 Dunn, 2004, The three Es of cancer immunoediting, Annu. Rev. Immunol., 22, 329, 10.1146/annurev.immunol.22.012703.104803 Yu, 2009, STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer, 9, 798, 10.1038/nrc2734 Ruffell, 2015, Macrophages and therapeutic resistance in cancer, Cancer Cell, 27, 462, 10.1016/j.ccell.2015.02.015 Grivennikov, 2009, IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer, Cancer Cell, 15, 103, 10.1016/j.ccr.2009.01.001 Taniguchi, 2018, NF-κB, inflammation, immunity and cancer: coming of age, Nat. Rev. Immunol., 18, 309, 10.1038/nri.2017.142 Huynh, 2019, Therapeutically exploiting STAT3 activity in cancer—using tissue repair as a road map, Nat. Rev. Cancer, 19, 82, 10.1038/s41568-018-0090-8 Kelly-Spratt, 2011, Plasma proteome profiles associated with inflammation, angiogenesis, and cancer, PLoS ONE, 6, 10.1371/journal.pone.0019721 Allavena, 2008, Pathways connecting inflammation and cancer, Curr. Opin. Genet. Dev., 18, 3, 10.1016/j.gde.2008.01.003 Khandia, 2020, Interplay between inflammation and cancer, 199 Doedens, 2010, Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression, Cancer Res., 70, 7465, 10.1158/0008-5472.CAN-10-1439 Noman, 2015, Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia, Am. J. Physiol. Cell Physiol., 309, C569, 10.1152/ajpcell.00207.2015 Chang, 2019, A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers, J. Translational Med., 17, 14, 10.1186/s12967-019-1775-9 Wattenberg, 2020, Overcoming immunotherapeutic resistance by targeting the cancer inflammation cycle Solinas, 2009, Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation, J. Leukoc. Biol., 86, 1065, 10.1189/jlb.0609385 DeNardo, 2019, Macrophages as regulators of tumour immunity and immunotherapy, Nat. Rev. Immunol., 19, 369, 10.1038/s41577-019-0127-6 Chow, 2014, Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB, Sci. Rep., 4, 1, 10.1038/srep05750 Jones, 2016, STAT3 establishes an immunosuppressive microenvironment during the early stages of breast carcinogenesis to promote tumor growth and metastasis, Cancer Res., 76, 1416, 10.1158/0008-5472.CAN-15-2770 Wynn, 2016, Macrophages in tissue repair, regeneration, and fibrosis, Immunity, 44, 450, 10.1016/j.immuni.2016.02.015 Sharda, 2011, Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase, J. Immunol., 187, 2181, 10.4049/jimmunol.1003460 Tan, 2018, Inhibition of Rspo-Lgr4 facilitates checkpoint blockade therapy by switching macrophage polarization, Cancer Res., 78, 4929, 10.1158/0008-5472.CAN-18-0152 Iliopoulos, 2010, STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer, Mol. Cell, 39, 493, 10.1016/j.molcel.2010.07.023 Paladini, 2016, Targeting microRNAs as key modulators of tumor immune response, J. Exp. Clin. Cancer Res., 35, 103, 10.1186/s13046-016-0375-2 Santoni, 2018, Triple negative breast cancer: key role of tumor-associated macrophages in regulating the activity of anti-PD-1/PD-L1 agents, Biochimica et Biophysica Acta (BBA)-Reviews on, Cancer, 1869, 78 Ruffell, 2014, Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells, Cancer Cell, 26, 623, 10.1016/j.ccell.2014.09.006 Takeda, 2010, Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis, Genes Dev., 24, 491, 10.1101/gad.1881410 Cho, 2018, Pro-inflammatory M1 Macrophage enhances metastatic potential of ovarian cancer cells through NF-κB activation, Mol. Carcinog., 57, 235, 10.1002/mc.22750 Qian, 2020, Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-κB pathways, Oncogene, 39, 428, 10.1038/s41388-019-0996-y Behdani, 2019, RNA-Seq Bayesian Network Exploration of Immune System in Bovine, Iran. J. Biotechnol., 17, 10.29252/ijb.1748 Cheng, 2020, Exosomal noncoding RNAs in Glioma: biological functions and potential clinical applications, Mol. Cancer, 19, 1, 10.1186/s12943-020-01189-3 Kaneda, 2016, PI3Kγ is a molecular switch that controls immune suppression, Nature, 539, 437, 10.1038/nature19834 Yue, 2015, Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer, Exp. Cell Res., 336, 141, 10.1016/j.yexcr.2015.06.007 Fu, 2020, The roles of tumor-associated macrophages in tumor angiogenesis and metastasis, Cell. Immunol., 104119 Qiao, 2020, Macrophages confer resistance to BET inhibition in triple-negative breast cancer by upregulating IKBKE, Biochem. Pharmacol., 114126 Guo, 2013, IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer, Oncogene, 32, 151, 10.1038/onc.2012.39 Powell, 2016, Neutrophils in the tumor microenvironment, Trends Immunol., 37, 41, 10.1016/j.it.2015.11.008 Giese, 2019, Neutrophil plasticity in the tumor microenvironment, Blood, 133, 2159, 10.1182/blood-2018-11-844548 Ohms, 2020, An attempt to polarize human neutrophils toward N1 and N2 phenotypes in vitro, Front. Immunol., 11, 10.3389/fimmu.2020.00532 Albini, 2018, Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy, Front. Immunol., 9, 527, 10.3389/fimmu.2018.00527 Deryugina, 2014, Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment, Neoplasia, 16, 771, 10.1016/j.neo.2014.08.013 Ostanin, 2012, Acquisition of antigen-presenting functions by neutrophils isolated from mice with chronic colitis, J. Immunol., 188, 1491, 10.4049/jimmunol.1102296 Jönsson, 2011, Mouse and human neutrophils induce anaphylaxis, J. Clin. Investig., 121, 1484, 10.1172/JCI45232 Puga, 2012, B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen, Nat. Immunol., 13, 170, 10.1038/ni.2194 Pillay, 2012, A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1, J. Clin. Investig., 122, 327, 10.1172/JCI57990 Marwick, 2018, Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-κB activation, Cell Death Dis., 9, 1, 10.1038/s41419-018-0710-y De Santo, 2010, Invariant NKT cells modulate the suppressive activity of Serum Amyloid A-differentiated IL-10-secreting neutrophils, Nat. Immunol., 11, 1039, 10.1038/ni.1942 Zhou, 2019, A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression, Hepatology, 70, 1214, 10.1002/hep.30630 Yamanaka, 2020, Subquinocin, a small molecule inhibitor of CYLD and USP-family deubiquitinating enzymes, promotes NF-κB signaling, Biochem. Biophys. Res. Commun., 524, 1, 10.1016/j.bbrc.2019.12.049 Yuan, 2020, Reduced expression of CYLD promotes cell survival and inflammation in gefitinib-treated NSCLC PC-9 cells: targeting CYLD may be beneficial for acquired resistance to gefitinib therapy, Cell Biol. Int., 10.1002/cbin.11397 Sasaki, 2018, Involvement of prokineticin 2–expressing neutrophil infiltration in 5-fluorouracil–induced aggravation of breast cancer metastasis to lung, Mol. Cancer Ther., 17, 1515, 10.1158/1535-7163.MCT-17-0845 Saini, 2019, Circulating tumor cell-neutrophil tango along the metastatic process, Cancer Res., 79, 6067, 10.1158/0008-5472.CAN-19-1972 Nishida, 2020, Epigenetic remodelling shapes inflammatory renal cancer and neutrophil-dependent metastasis, Nat. Cell Biol., 22, 465, 10.1038/s41556-020-0491-2 Zhou, 2016, Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib, Gastroenterology, 150, 1646, 10.1053/j.gastro.2016.02.040 Mishalian, 2014, Neutrophils recruit regulatory T-cells into tumors via secretion of CCL17—A new mechanism of impaired antitumor immunity, Int. J. Cancer, 135, 1178, 10.1002/ijc.28770 Liu, 2019, Recent advances in the study of regulatory T cells in gastric cancer, Int. Immunopharmacol., 73, 560, 10.1016/j.intimp.2019.05.009 Hwang, 2019, Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer, J. Hematol. Oncol., 12, 10, 10.1186/s13045-019-0699-4 Li, 2017, Interleukin-17–producing neutrophils link inflammatory stimuli to disease progression by promoting angiogenesis in gastric cancer, Clin. Cancer Res., 23, 1575, 10.1158/1078-0432.CCR-16-0617 Li, 2019, Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells, J. Exp. Clin. Cancer Res., 38, 6, 10.1186/s13046-018-1003-0 Wang, 2020, Th17 cells inhibit CD8+ T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients, J. Hematol. Oncol., 13, 1, 10.1186/s13045-020-00897-z Lee, 2019, Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum, J. Exp. Med., 216, 176, 10.1084/jem.20181170 Nie, 2019, Neutrophil extracellular traps induced by IL8 promote diffuse large B-cell lymphoma progression via the TLR9 signaling, Clin. Cancer Res., 25, 1867, 10.1158/1078-0432.CCR-18-1226 Teijeira, 2020, Cxcr1 and cxcr2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity, Immunity, 10.1016/j.immuni.2020.03.001 Schauer, 2014, Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines, Nat. Med., 20, 511, 10.1038/nm.3547 Cassetta, 2019, Deciphering myeloid-derived suppressor cells: isolation and markers in humans, mice and non-human primates, Cancer Immunol. Immunother., 68, 687, 10.1007/s00262-019-02302-2 Trovato, 2019, Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3, J. ImmunoTher. Cancer, 7, 255, 10.1186/s40425-019-0734-6 Kumar, 2016, The nature of myeloid-derived suppressor cells in the tumor microenvironment, Trends Immunol., 37, 208, 10.1016/j.it.2016.01.004 Li, 2020, Chemokines and their receptors promoting the recruitment of myeloid-derived suppressor cells into the tumor, Mol. Immunol., 117, 201, 10.1016/j.molimm.2019.11.014 Shrihari, 2017, Dual role of inflammatory mediators in cancer, Ecancermedicalscience, 11, 10.3332/ecancer.2017.721 Obermajer, 2012, PGE2-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells, Immunol. Invest., 41, 635, 10.3109/08820139.2012.695417 Sanaei, 2020, Crosstalk between myeloid-derived suppressor cells and the immune system in prostate cancer: MDSCs and immune system in Prostate cancer, J. Leukoc. Biol., 107, 43, 10.1002/JLB.4RU0819-150RR Poschke, 2010, Immature immunosuppressive CD14+ HLA-DR−/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign, Cancer Res., 70, 4335, 10.1158/0008-5472.CAN-09-3767 Corzo, 2009, Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells, J. Immunol., 182, 5693, 10.4049/jimmunol.0900092 Kim, 2019, Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-κB signaling, Cancer Med., 8, 276, 10.1002/cam4.1878 Gabrilovich, 2012, Coordinated regulation of myeloid cells by tumours, Nat. Rev. Immunol., 12, 253, 10.1038/nri3175 Binsfeld, 2016, Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma, Oncotarget, 7, 37931, 10.18632/oncotarget.9270 Rébé, 2020, Interleukin-1β and Cancer, Cancers, 12, 1791, 10.3390/cancers12071791 Shibata, 2019, Correlation of inflammation-related markers with MDSC and IL-17, and use as prognostic indicators in patients with advanced gastric and colorectal cancers, Am. Soc. Clin. Oncol., 10.1200/JCO.2019.37.15_suppl.e14204 Meyer, 2011, Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model, Proc. Natl. Acad. Sci., 108, 17111, 10.1073/pnas.1108121108 Dickinson, 2019, TLR4 in skin cancer: From molecular mechanisms to clinical interventions, Mol. Carcinog., 58, 1086, 10.1002/mc.23016 Fleming, 2019, Melanoma extracellular vesicles generate immunosuppressive myeloid cells by upregulating PD-L1 via TLR4 signaling, Cancer Res., 79, 4715, 10.1158/0008-5472.CAN-19-0053 Cheng, 2008, Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein, J. Exp. Med., 205, 2235, 10.1084/jem.20080132 Giallongo, 2016, Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC), Oncotarget, 7, 85764, 10.18632/oncotarget.7969 De Veirman, 2015, Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells, Oncotarget, 6, 10532, 10.18632/oncotarget.3300 Ozerova, 2019, Estrogen promotes multiple myeloma through enhancing the immunosuppressive activity of MDSC, Leukemia Lymphoma, 60, 1557, 10.1080/10428194.2018.1538511 Geis-Asteggiante, 2018, Differential content of proteins, mRNAs, and miRNAs suggests that MDSC and their exosomes may mediate distinct immune suppressive functions, J. Proteome Res., 17, 486, 10.1021/acs.jproteome.7b00646 Wang, 2019, Granulocytic myeloid-derived suppressor cells promote the stemness of colorectal cancer cells through exosomal S100A9, Adv. Sci., 6, 1901278, 10.1002/advs.201901278 Lang, 2019, Inflammasome signaling mediates myeloid immunosuppression within the tumor microenvironment, Am. Assoc. Immnol. Corzo, 2010, HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment, J. Exp. Med., 207, 2439, 10.1084/jem.20100587 Ke, 2020, PAR2 deficiency enhances myeloid cell-mediated immunosuppression and promotes colitis-associated tumorigenesis, Cancer Lett., 469, 437, 10.1016/j.canlet.2019.11.015 Gabrilovich, 2009, Myeloid-derived suppressor cells as regulators of the immune system, Nat. Rev. Immunol., 9, 162, 10.1038/nri2506 Choi, 2019, IL-12 enhances immune response by modulation of myeloid derived suppressor cells in tumor microenvironment, Chonnam Med. J., 55, 31, 10.4068/cmj.2019.55.1.31 Di Conza, 2017, The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia, Cell Rep., 18, 1699, 10.1016/j.celrep.2017.01.051 Wang, 2020, PHD2 exerts anti-cancer and anti-inflammatory effects in colon cancer xenografts mice via attenuating NF-κB activity, Life Sci., 242, 10.1016/j.lfs.2019.117167 Becher, 2016, GM-CSF: from growth factor to central mediator of tissue inflammation, Immunity, 45, 963, 10.1016/j.immuni.2016.10.026 Lin, 2017, Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation, Oncogene, 36, 3599, 10.1038/onc.2016.516 Liu, 2020, Anticancer Effects of ACT001 via NF-κB Suppression in Murine Triple-Negative Breast Cancer Cell Line 4T1, Cancer Manage. Res., 12, 5131, 10.2147/CMAR.S244748 Xi, 2019, Pharmacokinetics, tissue distribution and excretion of ACT001 in Sprague-Dawley rats and metabolism of ACT001, J. Chromatogr. B, 1104, 29, 10.1016/j.jchromb.2018.11.004 Xi, 2019, ACT001, a novel PAI-1 inhibitor, exerts synergistic effects in combination with cisplatin by inhibiting PI3K/AKT pathway in glioma, Cell Death Dis., 10, 1, 10.1038/s41419-019-1986-2 Tanaka, 2014, IL-6 in inflammation, immunity, and disease, Cold Spring Harbor Perspect. Biol., 6, 10.1101/cshperspect.a016295 Johnson, 2018, Targeting the IL-6/JAK/STAT3 signalling axis in cancer, Nat. Rev. Clin. Oncol., 15, 234, 10.1038/nrclinonc.2018.8 Ham, 2018, Breast cancer-derived exosomes alter macrophage polarization via gp130/STAT3 signaling, Front. Immunol., 9, 871, 10.3389/fimmu.2018.00871 Jones, 2018, IL-27: a double agent in the IL-6 family, Clin. Exp. Immunol., 193, 37, 10.1111/cei.13116 Li, 2018, Down-regulating IL-6/GP130 targets improved the anti-tumor effects of 5-fluorouracil in colon cancer, Apoptosis, 23, 356, 10.1007/s10495-018-1460-0 Hossain, 2013, FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells, Immunity, 39, 1057, 10.1016/j.immuni.2013.11.005 Liu, 2019, CKLF1 enhances inflammation-mediated carcinogenesis and prevents doxorubicin-induced apoptosis via IL6/STAT3 signaling in HCC, Clin. Cancer Res., 25, 4141, 10.1158/1078-0432.CCR-18-3510 Ohno, 2017, Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy, Cancer Sci., 108, 1959, 10.1111/cas.13330 Mirzaei, 2019, Inflammatory pathway interactions and cancer multidrug resistance regulation, Life Sci., 116825 Jiang, 2019, The relationship between autophagy and the immune system and its applications for tumor immunotherapy, Mol. Cancer, 18, 17, 10.1186/s12943-019-0944-z Lu, 2018, Role of IL-6-mediated expression of NS5ATP9 in autophagy of liver cancer cells, J. Cell. Physiol., 233, 9312, 10.1002/jcp.26343 Wang, 2018, Interleukin-6 contributes to chemoresistance in MDA-MB-231 cells via targeting HIF-1α, J. Biochem. Mol. Toxicol., 32, 10.1002/jbt.22039 Kuo, 2017, STAT3/NF-κB-regulated lentiviral TK/GCV suicide gene therapy for cisplatin-resistant triple-negative breast cancer, Theranostics, 7, 647, 10.7150/thno.16827 Hartman, 2013, Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8, Cancer Res., 73, 3470, 10.1158/0008-5472.CAN-12-4524-T Koliaraki, 2015, IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer, J. Exp. Med., 212, 2235, 10.1084/jem.20150542 Wang, 2017, TWEAK/Fn14 promotes pro-inflammatory cytokine secretion in hepatic stellate cells via NF-κB/STAT3 pathways, Mol. Immunol., 87, 67, 10.1016/j.molimm.2017.04.003 P. Lopez-Bergami, G. Barbero, The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment, Cancer Metastasis Rev. (2020). Sziksz, 2015, Fibrosis related inflammatory mediators: role of the IL-10 cytokine family, Mediators Inflamm., 2015, 10.1155/2015/764641 Hsu, 2015, IL-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1, J. Immunol., 195, 3665, 10.4049/jimmunol.1402898 Chaudhry, 2011, Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation, Immunity, 34, 566, 10.1016/j.immuni.2011.03.018 Shouval, 2014, Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function, Immunity, 40, 706, 10.1016/j.immuni.2014.03.011 Coccia, 2012, IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells, J. Exp. Med., 209, 1595, 10.1084/jem.20111453 M. Saraiva, A. O'garra, The regulation of IL-10 production by immune cells, Nat. Rev. Immunol. 10(3) (2010) 170–181. Sun, 2020, β7 integrin inhibition can increase intestinal inflammation by impairing homing of CD25hiFoxP3+ regulatory T cells, Cellular Mol. Gastroenterol. Hepatol., 9, 369, 10.1016/j.jcmgh.2019.10.012 Lee, 2010, NDRG2-mediated modulation of SOCS3 and STAT3 activity inhibits IL-10 production, Immune Netw., 10, 219, 10.4110/in.2010.10.6.219 Rottenberg, 2014, SOCS3, a major regulator of infection and inflammation, Front. Immunol., 5, 58 Tian, 2014, Targeting IL-10 in auto-immune diseases, Cell Biochem. Biophys., 70, 37, 10.1007/s12013-014-9903-x Yang, 2015, Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway, Med. Oncol., 32, 14, 10.1007/s12032-014-0352-6 Hutchins, 2013, The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges, Briefings Funct. Genom., 12, 489, 10.1093/bfgp/elt028 Zhang, 2016, Methane limit LPS-induced NF-κB/MAPKs signal in macrophages and suppress immune response in mice by enhancing PI3K/AKT/GSK-3β-mediated IL-10 expression, Sci. Rep., 6, 1 Li, 2016, Impaired T cell function in malignant pleural effusion is caused by TGF-β derived predominantly from macrophages, Int. J. Cancer, 139, 2261, 10.1002/ijc.30289 Neuzillet, 2015, Targeting the TGFβ pathway for cancer therapy, Pharmacol. Ther., 147, 22, 10.1016/j.pharmthera.2014.11.001 Meulmeester, 2011, The dynamic roles of TGF-β in cancer, J. Pathol., 223, 206, 10.1002/path.2785 Chang, 2016, Role of immune cells in pancreatic cancer from bench to clinical application: an updated review, Medicine, 95, 10.1097/MD.0000000000005541 Xu, 2016, TGF-β/SMAD pathway and its regulation in hepatic fibrosis, J. Histochem. Cytochem., 64, 157, 10.1369/0022155415627681 Bertran, 2013, Overactivation of the TGF-β pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells, Hepatology, 58, 2032, 10.1002/hep.26597 Principe, 2014, TGF-β: duality of function between tumor prevention and carcinogenesis, JNCI: J. Natl. Cancer Inst., 106, 10.1093/jnci/djt369 Asiedu, 2011, TGFβ/TNFα-mediated epithelial–mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype, Cancer Res., 71, 4707, 10.1158/0008-5472.CAN-10-4554 Xu, 2018, TGF-β plays a vital role in triple-negative breast cancer (TNBC) drug-resistance through regulating stemness, EMT and apoptosis, Biochem. Biophys. Res. Commun., 502, 160, 10.1016/j.bbrc.2018.05.139 Li, 2019, NF-κB/Twist axis is involved in chysin inhibition of ovarian cancer stem cell features induced by co-treatment of TNF-α and TGF-β, Int. J. Clin. Exp. Path., 12, 101 Fuxe, 2012, TGF-β-induced epithelial-mesenchymal transition: a link between cancer and inflammation, 455 Maier, 2010, NF-κB promotes epithelial–mesenchymal transition, migration and invasion of pancreatic carcinoma cells, Cancer Lett., 295, 214, 10.1016/j.canlet.2010.03.003 Liu, 2014, JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells, Int. J. Oncol., 44, 1643, 10.3892/ijo.2014.2310 Q. Liu, D. Tong, G. Liu, J. Xu, K. Do, K. Geary, D. Zhang, J. Zhang, Y. Zhang, Y. Li, Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β 1/STAT3 axis-regulated EMT, Cell Death Dis. 8(8) (2017) e3007–e3007. Sun, 2013, Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression, Mol. Cancer Ther., 12, 2885, 10.1158/1535-7163.MCT-12-1087 Tang, 2017, Transforming growth factor-β (TGF-β) directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway, J. Biol. Chem., 292, 4302, 10.1074/jbc.M116.773085