159
Views
37
CrossRef citations to date
0
Altmetric
Review

Targeting myeloid-derived suppressor cells in the treatment of hepatocellular carcinoma: current state and future perspectives

, &
Pages 71-84 | Published online: 07 May 2019

References

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.2149230207593
  • Hsiue EH-CH, Lo W-C, Lin -H-H, Hsu C-H, Cheng A-L. Abstract 286: forecast of the incidence and etiology of liver cancer in Taiwan, Japan, United States, and United Kingdom: toward harmonization of East and West. Cancer Res. 2017;77(13 Supplement):286. doi:10.1158/1538-7445.AM2017-286
  • Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–1314. doi:10.1016/S0140-6736(18)30010-229307467
  • Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa070885718650514
  • Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. doi:10.1016/S1470-2045(08)70285-719095497
  • Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. doi:10.1016/S0140-6736(16)32453-927932229
  • Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–1173. doi:10.1016/S0140-6736(18)30207-129433850
  • Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63. doi:10.1056/NEJMoa171700229972759
  • Zhu AX, Kang Y-K, Yen C-J, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol 2018;36(15_suppl):4003.
  • El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–2502. doi:10.1016/S0140-6736(17)31046-2.28434648
  • Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–952.29875066
  • Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018;15(5):310–324. doi:10.1038/nrclinonc.2018.929434333
  • Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15(5):325–340. doi:10.1038/nrclinonc.2018.2929508855
  • Xu J-M, Zhang Y, Jia R, et al. Anti-programmed death-1 antibody SHR-1210 (S) combined with apatinib (A) for advanced hepatocellular carcinoma (HCC), gastric cancer (GC) or esophagogastric junction (EGJ) cancer refractory to standard therapy: a phase 1 trial. J Clin Oncol. 2018;36(15_suppl):4075. doi:10.1200/JCO.2018.36.15_suppl.4075
  • Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36(15_suppl):4076. doi:10.1200/JCO.2018.36.15_suppl.4076
  • Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36(15_suppl):4074. doi:10.1200/JCO.2018.36.15_suppl.4074
  • Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5(1):3–8. doi:10.1158/2326-6066.CIR-16-029728052991
  • Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150. doi:10.1038/ncomms1215027381735
  • Condamine T, Dominguez GA, Youn JI, et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol. 2016;1:2. doi:10.1126/sciimmunol.aah6817
  • Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–174. doi:10.1038/nri250619197294
  • Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8(8):618–631. doi:10.1038/nrc244418633355
  • 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(23):19574–19584. doi:10.1074/jbc.M111.32680122528488
  • Shojaei F, Wu X, Malik AK, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol. 2007;25(8):911–920. doi:10.1038/nbt132317664940
  • Shojaei F, Wu X, Qu X, et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A. 2009;106(16):6742–6747. doi:10.1073/pnas.090228010619346489
  • Ahn GO, Brown JM. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell. 2008;13(3):193–205. doi:10.1016/j.ccr.2007.11.03218328424
  • Yang L, DeBusk LM, Fukuda K, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;6(4):409–421. doi:10.1016/j.ccr.2004.08.03115488763
  • Lj P, Us G, Quaglia A, et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med. 2015;21(6):591–600. doi:10.1038/nm.385625962123
  • Goh CC, Roggerson KM, Lee HC, Golden-Mason L, Rosen HR, Hahn YS. Hepatitis C virus-induced myeloid-derived suppressor cells suppress NK cell IFN-gamma production by altering cellular metabolism via arginase-1. J Immunol. 2016;196(5):2283–2292. doi:10.4049/jimmunol.150188126826241
  • Tacke RS, Lee HC, Goh C, et al. Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species. Hepatology. 2012;55(2):343–353. doi:10.1002/hep.2470021953144
  • Yao L, Abe M, Kawasaki K, et al. Characterization of liver monocytic myeloid-derived suppressor cells and their role in a murine model of non-alcoholic fatty liver disease. PLoS One. 2016;11(2):e0149948. doi:10.1371/journal.pone.014994826901500
  • Dandri M, Bockmann JH. The challenge of protecting without overprotecting: the two sides of myeloid-derived suppressor cells in hepatitis B viral infection. Hepatology. 2016;63(3):1043–1046. doi:10.1002/hep.2838526661682
  • Duffy A, Zhao F, Haile L, et al. Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal malignancies. Cancer Immunol Immunother. 2013;62(2):299–307. doi:10.1007/s00262-012-1332-323011590
  • Hoechst B, Ormandy LA, Ballmaier M, et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 2008;135(1):234–243. doi:10.1053/j.gastro.2008.03.02018485901
  • Arihara F, Mizukoshi E, Kitahara M, 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(8):1421–1430. doi:10.1007/s00262-013-1447-123764929
  • Gao XH, Tian L, Wu J, et al. Circulating CD14(+) HLA-DR(-/low) myeloid-derived suppressor cells predicted early recurrence of hepatocellular carcinoma after surgery. Hepatol Res. 2017;47(10):1061–1071. doi:10.1111/hepr.1283127764536
  • Mizukoshi E, Yamashita T, Arai K, et al. Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma. Cancer Immunol Immunother. 2016;65(6):715–725. doi:10.1007/s00262-016-1837-227083166
  • Iwata T, Kondo Y, Kimura O, et al. PD-L1(+)MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment. Sci Rep. 2016;6:39296. doi:10.1038/srep3929627966626
  • Hoechst B, Voigtlaender T, Ormandy L, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology. 2009;50(3):799–807. doi:10.1002/hep.2305419551844
  • Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013;73(8):2435–2444. doi:10.1158/0008-5472.CAN-12-338123423978
  • Nan J, Xing YF, Hu B, et al. Endoplasmic reticulum stress induced LOX-1(+) CD15(+) polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma. Immunology. 2018;154(1):144–155. doi:10.1111/imm.1287629211299
  • Kapanadze T, Gamrekelashvili J, Ma C, et al. Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J Hepatol. 2013;59(5):1007–1013. doi:10.1016/j.jhep.2013.06.01023796475
  • Hu CE, Gan J, Zhang RD, Cheng YR, Huang GJ. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol. 2011;46(2):156–164. doi:10.3109/00365521.2010.51645020822377
  • Lacotte S, Slits F, Orci LA, et al. Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma. Oncoimmunology. 2016;5(11):e1234565. doi:10.1080/2162402X.2016.123456527999748
  • Chen Y, Huang Y, Reiberger T, et al. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology. 2014;59(4):1435–1447. doi:10.1002/hep.2679024242874
  • Chang CJ, Yang YH, Chiu CJ, et al. Targeting tumor-infiltrating Ly6G(+) myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma. Int J Cancer. 2018;142(9):1878–1889. doi:10.1002/ijc.3121629266245
  • Chiu DK, Tse AP, Xu IM, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun. 2017;8(1):517. doi:10.1038/s41467-017-00530-728894087
  • Zhou J, Liu M, Sun H, et al. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut. 2018;67(5):931–944. doi:10.1136/gutjnl-2017-31403228939663
  • Fleming V, Hu X, Weber R, et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front Immunol. 2018;9:398. doi:10.3389/fimmu.2018.0039829552012
  • Medina-Echeverz J, Eggert T, Han M, Greten TF. Hepatic myeloid-derived suppressor cells in cancer. Cancer Immunol Immunother. 2015;64(8):931–940. doi:10.1007/s00262-015-1736-y26133122
  • De Sanctis F, Solito S, Ugel S, Molon B, Bronte V, Marigo I. MDSCs in cancer: conceiving new prognostic and therapeutic targets. Biochim Biophys Acta. 2016;1865(1):35–48. doi:10.1016/j.bbcan.2015.08.00126255541
  • Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G. Gemcitabine reduces MDSCs, tregs and TGFbeta-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med. 2016;14(1):282. doi:10.1186/s12967-016-0867-z27687804
  • Alizadeh D, Trad M, Hanke NT, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014;74(1):104–118. doi:10.1158/0008-5472.CAN-13-154524197130
  • Sevko A, Michels T, Vrohlings M, et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J Immunol. 2013;190(5):2464–2471. doi:10.4049/jimmunol.120278123359505
  • Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70(8):3052–3061. doi:10.1158/0008-5472.CAN-09-369020388795
  • Al C, Kh Y, Rl F, et al. Biochemical modulation of doxorubicin by high-dose tamoxifen in the treatment of advanced hepatocellular carcinoma. Hepatogastroenterology. 1998;45(24):1955–1960.9951847
  • Yang TS, Lin YC, Chen JS, Wang HM, Wang CH. Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer. 2000;89(4):750–756.10951336
  • Guan Z, Wang Y, Maoleekoonpairoj S, et al. Prospective randomised phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma. Br J Cancer. 2003;89(10):1865–1869. doi:10.1038/sj.bjc.660136914612894
  • Chao Y, Chan WK, Birkhofer MJ, et al. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer. 1998;78(1):34–39.9662247
  • Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988;62(3):479–483.2839280
  • Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97(20):1532–1538. doi:10.1093/jnci/dji31516234567
  • Gebbia V, Maiello E, Serravezza G, et al. 5-Fluorouracil plus high dose levofolinic acid and oral hydroxyurea for the treatment of primary hepatocellular carcinomas: results of a phase II multicenter study of the Southern Italy Oncology Group (G.O.I.M.). Anticancer Res. 1999;19(2B):1407–1410.10365114
  • Patt YZ, Hassan MM, Lozano RD, et al. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol. 2003;21(3):421–427. doi:10.1200/JCO.2003.10.10312560429
  • Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423–436. doi:10.1038/nrc136915170445
  • Chan TS, Hsu CC, Pai VC, et al. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med. 2016;213(13):2967–2988. doi:10.1084/jem.2015166527881732
  • Andre N, Tsai K, Carre M, Pasquier E. Metronomic chemotherapy: direct targeting of cancer cells after all? Trends Cancer. 2017;3(5):319–325. doi:10.1016/j.trecan.2017.03.01128718409
  • Abdel-Rahman O, Abdel-Wahab M, Shaker M, Abdel-Wahab S, Elbassiony M, Ellithy M. Sorafenib versus capecitabine in the management of advanced hepatocellular carcinoma. Med Oncol. 2013;30(3):655. doi:10.1007/s12032-013-0655-z23824645
  • Hsu CH, Shen YC, Lin ZZ, et al. Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. J Hepatol. 2010;53(1):126–131. doi:10.1016/j.jhep.2010.01.03520416968
  • Hsu CH, Yang TS, Hsu C, et al. Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br J Cancer. 2010;102(6):981–986. doi:10.1038/sj.bjc.660558020160718
  • Shao YY, Lin ZZ, Hsu C, et al. Efficacy, safety, and potential biomarkers of thalidomide plus metronomic chemotherapy for advanced hepatocellular carcinoma. Oncology. 2012;82(1):59–66. doi:10.1159/00033612622310088
  • Ko JS, Zea AH, Rini BI, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15(6):2148–2157. doi:10.1158/1078-0432.CCR-08-133219276286
  • Chen HM, Ma G, Gildener-Leapman N, et al. Myeloid-derived suppressor cells as an immune parameter in patients with concurrent sunitinib and stereotactic body radiotherapy. Clin Cancer Res. 2015;21(18):4073–4085. doi:10.1158/1078-0432.CCR-14-274225922428
  • Draghiciu O, Nijman HW, Hoogeboom BN, Meijerhof T, Daemen T. Sunitinib depletes myeloid-derived suppressor cells and synergizes with a cancer vaccine to enhance antigen-specific immune responses and tumor eradication. Oncoimmunology. 2015;4(3):e989764. doi:10.1080/2162402X.2015.100837125949902
  • Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009;69(6):2514–2522. doi:10.1158/0008-5472.CAN-08-470919276342
  • Lu X, Horner JW, Paul E, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017;543(7647):728–732. doi:10.1038/nature2167628321130
  • Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31(32):4067–4075. doi:10.1200/JCO.2012.45.837224081937
  • Condamine T, Kumar V, Ramachandran IR, et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014;124(6):2626–2639. doi:10.1172/JCI7405624789911
  • Dominguez GA, Condamine T, Mony S, 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(12):2942–2950. doi:10.1158/1078-0432.CCR-16-178427965309
  • Cheng AL, Kang YK, He AR, et al. Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: a phase 2 randomized study. J Hepatol. 2015;63(4):896–904. doi:10.1016/j.jhep.2015.06.00126071796
  • Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 2007;67(22):11021–11028. doi:10.1158/0008-5472.CAN-07-259318006848
  • Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006;66(18):9299–9307. doi:10.1158/0008-5472.CAN-06-169016982775
  • Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich D. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother. 2013;62(5):909–918. doi:10.1007/s00262-013-1396-823589106
  • Egyed M, Nyaradi A, Boros B, et al. [Successful treatment of hepatocellular carcinoma with All-trans-retinoic acid]. Orv Hetil. 1998;139(14):811–812.9569727
  • Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996;334(24):1561–1567. doi:10.1056/NEJM1996061333424028628336
  • Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med. 1999;340(13):1046–1047. doi:10.1056/NEJM19990401340131510189289
  • Takai K, Okuno M, Yasuda I, et al. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology. 2005;48(1):39–45.15785088
  • Shimizu M, Imai K, Takai K, Moriwaki H. Role of acyclic retinoid in the chemoprevention of hepatocellular carcinoma: basic aspects, clinical applications, and future prospects. Curr Cancer Drug Targets. 2012;12(9):1119–1128.22873214
  • Ugel S, De Sanctis F, Mandruzzato S, Bronte V. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest. 2015;125(9):3365–3376.26325033
  • Lesokhin AM, Hohl TM, Kitano S, 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(4):876–886.22174368
  • Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016;17(5):651–662.27055731
  • 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(12):1949–1953.30232521
  • Blattner C, Fleming V, Weber R, et al. CCR5(+) myeloid-derived suppressor cells are enriched and activated in melanoma lesions. Cancer Res. 2018;78(1):157–167.29089297
  • Hawila E, Razon H, Wildbaum G, et al. CCR5 directs the mobilization of CD11b(+)Gr1(+)Ly6C(low) polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep. 2017;21(8):2212–2222.29166611
  • Le D, Gutierrez ME, Saleh M, et al. Abstract CT124: a phase Ib/II study of BMS-813160, a CC chemokine receptor (CCR) 2/5 dual antagonist, in combination with chemotherapy or nivolumab in patients (pts) with advanced pancreatic or colorectal cancer. Cancer Res. 2018;78(13 Supplement):CT124–CT124.
  • Highfill SL, Cui Y, Giles AJ, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014;6(237):237ra267.
  • Nywening TM, Belt BA, Cullinan DR, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut. 2018;67(6):1112–1123.29196437
  • ClincalTrials.gov. [ Updated 3 6, 2017; cited 1214, 2018]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT01839604. Accessed 1214, 2018.
  • Cohen EEW, Harrington KJ, Hong DS, et al. 1044OA phase Ib/II study (SCORES) of durvalumab (D) plus danvatirsen (DAN; AZD9150) or AZD5069 (CX2i) in advanced solid malignancies and recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC): updated results. Ann Oncol. 2018;29(suppl_8):mdy287.
  • Orillion A, Hashimoto A, Damayanti N, 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(17):5187–5201.28698201
  • Yeo W, Chung HC, Chan SL, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol. 2012;30(27):3361–3367.22915658
  • Bitzer M, Horger M, Giannini EG, et al. Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma – the SHELTER study. J Hepatol. 2016;65(2):280–288. doi:10.1016/j.jhep.2016.02.04326952006
  • Serafini P, Meckel K, Kelso M, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006;203(12):2691–2702. doi:10.1084/jem.2006110417101732
  • Lin S, Wang J, Wang L, et al. Phosphodiesterase-5 inhibition suppresses colonic inflammation-induced tumorigenesis via blocking the recruitment of MDSC. Am J Cancer Res. 2017;7(1):41–52.28123846
  • Yu SJ, Ma C, Heinrich B, et al. Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J Hepatol. 2018 Epub ahead of print. doi:10.1016/j.jhep.2018.10.040
  • Weed DT, Vella JL, Reis IM, et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(1):39–48. doi:10.1158/1078-0432.CCR-14-171125320361
  • Califano JA, Khan Z, Noonan KA, et al. Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(1):30–38. doi:10.1158/1078-0432.CCR-14-171625564570
  • Hassel JC, Jiang H, Bender C, et al. Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe). Oncoimmunology. 2017;6(9):e1326440. doi:10.1080/2162402X.2017.132644028932631