1. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res 2004;10:4332-4341.
2. Mizukoshi E, Nakamoto Y, Arai K, Yamashita T, Sakai A, Sakai Y, et al. Comparative analysis of various tumor-associated antigenspecific t-cell responses in patients with hepatocellular carcinoma. Hepatology 2011;53:1206-1216.
4. Behboudi S, Boswell S, Williams R. Cell-mediated immune responses to alpha-fetoprotein and other antigens in hepatocellular carcinoma. Liver Int 2010;30:521-526.
5. Zhang HG, Chen HS, Peng JR, Shang XY, Zhang J, Xing Q, et al. Specific CD8(
+ )T-cell responses to HLA-A2 restricted MAGE-A3 p271-279 peptide in hepatocellular carcinoma patients without vaccination. Cancer Immunol Immunother 2007;56:1945-1954.
6. Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T, et al. Increase in CD14
+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol Immunother 2013;62:1421-1430.
8. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T-cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 2005;65:2457-2464.
10. Duffy AG, Ulahannan SV, Makorova-Rusher O, Rahma O, Wedemeyer H, Pratt D, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017;66:545-551.
12. Greten TF, Lai CW, Li G, Staveley-O'Carroll KF. Targeted and immune-based therapies for hepatocellular carcinoma. Gastroenterology 2019;156:510-524.
23. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016;7:12150.
25. Qu X, Zhuang G, Yu L, Meng G, Ferrara N. Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b
+Gr1
+ cells: key role of Stat3 signaling. J Biol Chem 2012;287:19574-19584.
26. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b
+Gr1
+ myeloid cells. Nat Biotechnol 2007;25:911-920.
29. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressor Gr
+CD11b
+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004;6:409-421.
31. Zhou J, Liu M, Sun H, Feng Y, Xu L, Chan AWH, et al. Hepatomaintrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut 2018;67:931-944.
32. Greten TF, Korangy F. CDK20 inhibition and immune checkpoint blockade: bringing cancer biology and tumour immunology together to develop novel treatment options for HCC. Gut 2018;67:783-784.
34. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(
+)CD25(
+) Foxp3(
+) T-cells. Gastroenterology 2008;135:234-243.
36. Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S, et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008;129:428-437.
38. Yu SJ, Ma C, Heinrich B, Brown ZJ, Sandhu M, Zhang Q, et al. Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J Hepatol 2019;70:449-457.
41. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T-cells and immune tolerance. Cell 2008;133:775-787.
42. Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G. Human CD4(
+)CD25(
+) regulatory, contact-dependent T-cells induce interleukin 10-producing, contact-independent type 1-like regulatory T-cells [corrected]. J Exp Med 2002;196:247-253.
43. Shevach EM. CD4
+ CD25
+ suppressor T-cells: more questions than answers. Nat Rev Immunol 2002;2:389-400.
44. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, et al. Regulatory T-cells suppress tumor-specific CD8 T-cell cytotoxicity through TGF-beta signals
in vivo. Proc Natl Acad Sci U S A 2005;102:419-424.
49. Baron U, Floess S, Wieczorek G, Baumann K, Grützkau A, Dong J, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T-cells from activated FOXP3(
+) conventional T-cells. Eur J Immunol 2007;37:2378-2389.
51. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3
+ regulatory T-cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006;12:5423-5434.
52. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H, et al. Prognostic value of tumor-infiltrating CD4
+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006;12:465-472.
53. Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, et al. Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 2005;41:722-730.
54. Yang XH, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H, et al. Increase of CD4
+ CD25
+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol 2006;45:254-262.
55. Shen X, Li N, Li H, Zhang T, Wang F, Li Q. Increased prevalence of regulatory T-cells in the tumor microenvironment and its correlation with TNM stage of hepatocellular carcinoma. J Cancer Res Clin Oncol 2010;136:1745-1754.
56. Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, et al. FOXP3
+ regulatory T-cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 2007;13:902-911.
57. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T-cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007;132:2328-2339.
58. Zheng C, Zheng L, Yoo JK, Guo H, Zhang Y, Guo X, et al. Landscape of infiltrating T-cells in liver cancer revealed by single-cell sequencing. Cell 2017;169:1342-1356 e1316.
59. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, et al. Intratumoral balance of regulatory and cytotoxic T-cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007;25:2586-2593.
60. Zhou J, Ding T, Pan W, Zhu LY, Li L, Zheng L. Increased intratumoral regulatory T-cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer 2009;125:1640-1648.
61. Yang ZQ, Yang ZY, Zhang LD, Wang SG, Ma KS, et al. Increased liver-infiltrating CD8
+FoxP3
+ regulatory T-cells are associated with tumor stage in hepatocellular carcinoma patients. Hum Immunol 2010;71:1180-1186.
62. Greten TF, Ormandy LA, Fikuart A, Höchst B, Henschen S, Hörning M, et al. Low-dose cyclophosphamide treatment impairs regulatory T-cells and unmasks AFP-specific CD4
+ T-cell responses in patients with advanced HCC. J Immunother 2010;33:211-218.
64. Movahedi K, Van Ginderachter JA. The ontogeny and microenvironmental regulation of tumor-associated macrophages. Antioxid Redox Signal 2016;25:775-791.
66. Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun 2016;7:10321.
68. Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 2014;59:2034-2042.
69. Devisscher L, Scott CL, Lefere S, Raevens S, Bogaerts E, Paridaens A, et al. Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool. Cell Immunol 2017;322:74-83.
71. Aravalli RN. Role of innate immunity in the development of hepatocellular carcinoma. World J Gastroenterol 2013;19:7500-7514.
72. Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol 2011;21:35-43.
74. Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8
+ T-cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res 2009;69:8067-8075.
76. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011;331:1565-1570.
77. Laoui D, Van Overmeire E, Movahedi K, Van den Bossche J, Schouppe E, Mommer C, et al. Mononuclear phagocyte heterogeneity in cancer: different subsets and activation states reaching out at the tumor site. Immunobiology 2011;216:1192-1202.
79. Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 2006;66:11238-11246.
81. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005;8:211-226.
82. Murdoch C, Tazzyman S, Webster S, Lewis CE. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol 2007;178:7405-7411.
85. Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, et al. Tumor- associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 2016;150:1646-1658 e1617.
86. Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol 2011;54:948-955.
87. Zhou SL, Dai Z, Zhou ZJ, Wang XY, Yang GH, Wang Z, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 2012;56:2242-2254.
89. Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 2010;51:154-164.
90. Kuang DM, Peng C, Zhao Q, Wu Y, Zhu LY, Wang J, et al. Tumoractivated monocytes promote expansion of IL-17-producing CD8
+ T-cells in hepatocellular carcinoma patients. J Immunol 2010;185:1544-1549.
91. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 2009;50:980-989.
92. Zhao F, Hoechst B, Gamrekelashvili J, Ormandy LA, Voigtländer T, Wedemeyer H, et al. Human CCR4
+ CCR6
+ Th17 cells suppress autologous CD8
+ T-cell responses. J Immunol 2012;188:6055-6062.
93. Höchst B, Schildberg FA, Böttcher J, Metzger C, Huss S, Türler A, et al. Liver sinusoidal endothelial cells contribute to CD8 T-cell tolerance toward circulating carcinoembryonic antigen in mice. Hepatology 2012;56:1924-1933.
94. Carambia A, Freund B, Schwinge D, Heine M, Laschtowitz A, Huber S, et al. TGF-β-dependent induction of CD4
+CD25
+Foxp3
+ Tregs by liver sinusoidal endothelial cells. J Hepatol 2014;61:594-599.
96. Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, et al. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 2004;40:1312-1321.
98. Orillion A, Hashimoto A, Damayanti N, Shen L, Adelaiye-Ogala R, Arisa S, et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res 2017;23:5187-5201.
100. Bitzer M, Horger M, Giannini EG, Ganten TM, Wörns MA, Siveke JT, et al. Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study. J Hepatol 2016;65:280-288.
101. Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM. Mechanism of immune dysfunction in cancer mediated by immature Gr-1
+ myeloid cells. J Immunol 2001;166:5398-5406.
102. Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N, et al. Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol 2009;9:470-481.
104. Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T-cells from tumor-bearing mice. Int Immunopharmacol 2009;9:900-909.
105. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54-63.
108. Dominguez GA, Condamine T, Mony S, Hashimoto A, Wang F, Liu Q, et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin Cancer Res 2017;23:2942-2950.
110. Lesokhin AM, Hohl TM, Kitano S, Cortez C, Hirschhorn-Cymerman D, Avogadri F, et al. Monocytic CCR2(
+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res 2012;72:876-886.
111. Karin N, Razon H. The role of CCR5 in directing the mobilization and biological function of CD11b(
+)Gr1(
+)Ly6C(low) polymorphonuclear myeloid cells in cancer. Cancer Immunol Immunother 2018;67:1949-1953.
113. Zhou S, Chen L, Qin J, Li R, Tao H, Zhen Z, et al. Depletion of CD4
+ CD25
+ regulatory T-cells promotes CCL21-mediated antitumor immunity. PLoS One 2013;8:e73952.
114. Kavanagh B, O'Brien S, Lee D, Hou Y, Weinberg V, Rini B, et al. CTLA4 blockade expands FoxP3
+ regulatory and activated effector CD4
+ T-cells in a dose-dependent fashion. Blood 2008;112:1175-1183.
116. O'Mahony D, Morris JC, Quinn C, Gao W, Wilson WH, Gause B, et al. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res 2007;13:958-964.
117. Ralph C, Elkord E, Burt DJ, O'Dwyer JF, Austin EB, Stern PL, et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res 2010;16:1662-1672.
118. Weber JS, Hamid O, Chasalow SD, Wu DY, Parker SM, Galbraith S, et al. Ipilimumab increases activated T-cells and enhances humoral immunity in patients with advanced melanoma. J Immunother 2012;35:89-97.
119. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. Fc-dependent depletion of tumor-infiltrating regulatory T-cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 2013;210:1695-1710.
120. Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3
+CD25
+CD4
+ regulatory T-cells. J Exp Med 2005;202:885-891.
124. Lesokhin AM, Callahan MK, Postow MA, Wolchok JD. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T-cell activation. Sci Transl Med 2015;7:280 sr1.
128. Kurose K, Ohue Y, Sato E, Yamauchi A, Eikawa S, Isobe M, et al. Increase in activated treg in TIL in lung cancer and
in vitro depletion of treg by ADCC using an antihuman CCR4 mAb (KM2760). J Thorac Oncol 2015;10:74-83.
129. Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, et al. Specific recruitment of CC chemokine receptor 4-positive regulatory T-cells in Hodgkin lymphoma fosters immune privilege. Cancer Res 2006;66:5716-5722.
131. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 2012;30:837-842.
132. Redjimi N, Raffin C, Raimbaud I, Pignon P, Matsuzaki J, Odunsi K, et al. CXCR3
+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res 2012;72:4351-4360.
135. Sun Z, Fourcade J, Pagliano O, Chauvin JM, Sander C, Kirkwood JM, et al. IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8
+ T Cells. Cancer Res 2015;75:1635-1644.
136. Vicari AP, Chiodoni C, Vaure C, Aït-Yahia S, Dercamp C, Matsos F, et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 2002;196:541-549.
140. Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumourinfiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 2017;66:157-167.
142. Teng KY, Han J, Zhang X, Hsu SH, He S, Wani NA, et al. Blocking the CCL2-CCR2 axis using CCL2-neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model. Mol Cancer Ther 2017;16:312-322.
144. Ao JY, Zhu XD, Chai ZT, Cai H, Zhang YY, Zhang KZ, et al. Colonystimulating factor 1 receptor blockade inhibits tumor growth by altering the polarization of tumor-associated macrophages in hepatocellular carcinoma. Mol Cancer Ther 2017;16:1544-1554.
146. Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8
+ T-cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One 2019;14:e0212513.
149. Lapeyre-Prost A, Terme M, Pernot S, Pointet AL, Voron T, Tartour E, et al. Immunomodulatory activity of VEGF in cancer. Int Rev Cell Mol Biol 2017;330:295-342.