Neutrophils as potential therapeutic targets in hepatocellular carcinoma.
Journal
Nature reviews. Gastroenterology & hepatology
ISSN: 1759-5053
Titre abrégé: Nat Rev Gastroenterol Hepatol
Pays: England
ID NLM: 101500079
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
accepted:
06
12
2021
pubmed:
14
1
2022
medline:
5
4
2022
entrez:
13
1
2022
Statut:
ppublish
Résumé
The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focus of cancer immunotherapy has been on interrupting immune checkpoints that suppress antitumour lymphocytes. As well as lymphocytes, the HCC environment includes numerous other immune cell types, among which neutrophils are emerging as an important contributor to the pathogenesis of HCC. A growing body of evidence supports neutrophils as key mediators of the immunosuppressive environment in which some cancers develop, as well as drivers of tumour progression. If neutrophils have a similar role in HCC, approaches that target or manipulate neutrophils might have therapeutic benefits, potentially including sensitization of tumours to conventional immunotherapy. Several neutrophil-directed therapies for patients with HCC (and other cancers) are now entering clinical trials. This Review outlines the evidence in support of neutrophils as drivers of HCC and details their mechanistic roles in development, progression and metastasis, highlighting the reasons that neutrophils are well worth investigating despite the challenges associated with studying them. Neutrophil-modulating anticancer therapies entering clinical trials are also summarized.
Identifiants
pubmed: 35022608
doi: 10.1038/s41575-021-00568-5
pii: 10.1038/s41575-021-00568-5
doi:
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
257-273Subventions
Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R023026/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT107492Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K0019494/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18342/A23390
Pays : United Kingdom
Informations de copyright
© 2022. Springer Nature Limited.
Références
Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).
pubmed: 33538338
doi: 10.3322/caac.21660
Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450–1462 (2019).
pubmed: 30970190
doi: 10.1056/NEJMra1713263
Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 7, 6 (2021).
pubmed: 33479224
doi: 10.1038/s41572-020-00240-3
Xu, J. Trends in liver cancer mortality among adults aged 25 and over in the United States, 2000–2016. NCHS Data Brief 314, 1–8 (2018).
Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).
pubmed: 29379119
doi: 10.1038/s41590-018-0044-z
Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).
pubmed: 21094463
doi: 10.1016/j.immuni.2010.11.011
Li, Y. et al. The regulatory roles of neutrophils in adaptive immunity. Cell Commun. Signal. 17, 147 (2019).
pubmed: 31727175
pmcid: 6854633
doi: 10.1186/s12964-019-0471-y
Rosales, C. Neutrophil: a cell with many roles in inflammation or several cell types? Front. Physiol. 9, 113 (2018).
pubmed: 29515456
pmcid: 5826082
doi: 10.3389/fphys.2018.00113
Liu, K., Wang, F.-S. & Xu, R. Neutrophils in liver diseases: pathogenesis and therapeutic targets. Cell. Mol. Immunol. 18, 38–44 (2021).
pubmed: 33159158
doi: 10.1038/s41423-020-00560-0
Brostjan, C. & Oehler, R. The role of neutrophil death in chronic inflammation and cancer. Cell Death Discov. 6, 26 (2020).
pubmed: 32351713
pmcid: 7176663
doi: 10.1038/s41420-020-0255-6
Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).
pubmed: 956397
pmcid: 333229
doi: 10.1172/JCI108517
Colotta, F., Re, F., Polentarutti, N., Sozzani, S. & Mantovani, A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 80, 2012–2020 (1992).
pubmed: 1382715
doi: 10.1182/blood.V80.8.2012.2012
Ballesteros, I. et al. Co-option of neutrophil fates by tissue environments. Cell 183, 1282–1297.e1 (2020).
pubmed: 33098771
doi: 10.1016/j.cell.2020.10.003
Shaul, M. E. & Fridlender, Z. G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 16, 601–620 (2019).
pubmed: 31160735
doi: 10.1038/s41571-019-0222-4
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
pubmed: 32402160
doi: 10.1056/NEJMoa1915745
El-Khoueiry, A. B. 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 389, 2492–2502 (2017).
pubmed: 28434648
pmcid: 7539326
doi: 10.1016/S0140-6736(17)31046-2
Finn, R. S. et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J. Clin. Oncol. 38, 193–202 (2020).
pubmed: 31790344
doi: 10.1200/JCO.19.01307
Finn, R. S. et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J. Clin. Oncol. 39, 267 (2021).
doi: 10.1200/JCO.2021.39.3_suppl.267
Carvalho, L. O., Aquino, E. N., Neves, A. C. & Fontes, W. The neutrophil nucleus and its role in neutrophilic function. J. Cell Biochem. 116, 1831–1836 (2015).
pubmed: 25727365
doi: 10.1002/jcb.25124
Daley, J. M., Thomay, A. A., Connolly, M. D., Reichner, J. S. & Albina, J. E. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J. Leukoc. Biol. 83, 64–70 (2008).
pubmed: 17884993
doi: 10.1189/jlb.0407247
Dumitru, C. A., Moses, K., Trellakis, S., Lang, S. & Brandau, S. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol. Immunother. 61, 1155–1167 (2012).
pubmed: 22692756
doi: 10.1007/s00262-012-1294-5
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).
pubmed: 28117416
pmcid: 5480600
doi: 10.1038/nrclinonc.2016.217
Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).
pubmed: 19732719
pmcid: 2754404
doi: 10.1016/j.ccr.2009.06.017
Blattner, C. et al. CCR5
pubmed: 29089297
doi: 10.1158/0008-5472.CAN-17-0348
Dumitru, C. A., Fechner, M. K., Hoffmann, T. K., Lang, S. & Brandau, S. A novel p38-MAPK signaling axis modulates neutrophil biology in head and neck cancer. J. Leukoc. Biol. 91, 591–598 (2012).
pubmed: 22262799
doi: 10.1189/jlb.0411193
Eruslanov, E. B. et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J. Clin. Invest. 124, 5466–5480 (2014).
pubmed: 25384214
pmcid: 4348966
doi: 10.1172/JCI77053
Fridlender, Z. G. et al. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS ONE 7, e31524 (2012).
pubmed: 22348096
pmcid: 3279406
doi: 10.1371/journal.pone.0031524
Haqqani, A. S., Sandhu, J. K. & Birnboim, H. C. Expression of interleukin-8 promotes neutrophil infiltration and genetic instability in mutatect tumors. Neoplasia 2, 561–568 (2000).
pubmed: 11228549
pmcid: 1508092
doi: 10.1038/sj.neo.7900110
He, G. et al. Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 34, 141 (2015).
pubmed: 26581194
pmcid: 4652417
doi: 10.1186/s13046-015-0256-0
Kuang, D. M. et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J. Hepatol. 54, 948–955 (2011).
pubmed: 21145847
doi: 10.1016/j.jhep.2010.08.041
Mishalian, I. et al. Neutrophils recruit regulatory T-cells into tumors via secretion of CCL17 — a new mechanism of impaired antitumor immunity. Int. J. Cancer 135, 1178–1186 (2014).
pubmed: 24501019
doi: 10.1002/ijc.28770
Munder, M. et al. Suppression of T-cell functions by human granulocyte arginase. Blood 108, 1627–1634 (2006).
pubmed: 16709924
doi: 10.1182/blood-2006-11-010389
Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).
pubmed: 25620698
doi: 10.1016/j.celrep.2014.12.039
Shaul, M. E. et al. Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: a transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology 5, e1232221 (2016).
pubmed: 27999744
pmcid: 5139653
doi: 10.1080/2162402X.2016.1232221
Toor, S. M. & Elkord, E. Comparison of myeloid cells in circulation and in the tumor microenvironment of patients with colorectal and breast cancers. J. Immunol. Res. 2017, 7989020 (2017).
pubmed: 29230424
pmcid: 5694573
doi: 10.1155/2017/7989020
Wu, P. et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity 40, 785–800 (2014).
pubmed: 24816404
pmcid: 4716654
doi: 10.1016/j.immuni.2014.03.013
Zhou, S. L. et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 150, 1646–1658.e1617 (2016).
pubmed: 26924089
doi: 10.1053/j.gastro.2016.02.040
Takeshima, T. et al. Key role for neutrophils in radiation-induced antitumor immune responses: potentiation with G-CSF. Proc. Natl Acad. Sci. USA 113, 11300–11305 (2016).
pubmed: 27651484
pmcid: 5056034
doi: 10.1073/pnas.1613187113
Rice, C. M. et al. Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression. Nat. Commun. 9, 5099 (2018).
pubmed: 30504842
pmcid: 6269473
doi: 10.1038/s41467-018-07505-2
Kusmartsev, S., Nefedova, Y., Yoder, D. & Gabrilovich, D. I. Antigen-specific inhibition of CD8
pubmed: 14707072
doi: 10.4049/jimmunol.172.2.989
Ramachandran, P., Matchett, K. P., Dobie, R., Wilson-Kanamori, J. R. & Henderson, N. C. Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis. Nat. Rev. Gastroenterol. Hepatol. 17, 457–472 (2020).
pubmed: 32483353
doi: 10.1038/s41575-020-0304-x
Brunner, A.-D. et al. Ultra-high sensitivity mass spectrometry quantifies single-cell proteome changes upon perturbation. Preprint at bioRxiv https://doi.org/10.1101/2020.12.22.423933 (2020).
Schoof, E. M. et al. Quantitative single-cell proteomics as a tool to characterize cellular hierarchies. Nat. Commun. 12, 3341 (2021).
pubmed: 34099695
pmcid: 8185083
doi: 10.1038/s41467-021-23667-y
Baharlou, H., Canete, N. P., Cunningham, A. L., Harman, A. N. & Patrick, E. Mass cytometry imaging for the study of human diseases-applications and data analysis strategies. Front. Immunol. 10, 2657 (2019).
pubmed: 31798587
pmcid: 6868098
doi: 10.3389/fimmu.2019.02657
Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).
pubmed: 28052991
pmcid: 5426480
doi: 10.1158/2326-6066.CIR-16-0297
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
pubmed: 19197294
pmcid: 2828349
doi: 10.1038/nri2506
Lang, S. et al. Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin. Cancer Res. 24, 4834–4844 (2018).
pubmed: 29914893
doi: 10.1158/1078-0432.CCR-17-3726
Liu, C. Y. et al. Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b
pubmed: 19572148
doi: 10.1007/s00432-009-0634-0
Zea, A. H. et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 65, 3044–3048 (2005).
pubmed: 15833831
doi: 10.1158/0008-5472.CAN-04-4505
Veglia, F. et al. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 569, 73–78 (2019).
pubmed: 30996346
pmcid: 6557120
doi: 10.1038/s41586-019-1118-2
Mackey, J. B. G., Coffelt, S. B. & Carlin, L. M. Neutrophil maturity in cancer. Front. Immunol. 10, 1912 (2019).
pubmed: 31474989
pmcid: 6702268
doi: 10.3389/fimmu.2019.01912
Casbon, A.-J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl Acad. Sci. USA 112, E566–E575 (2015).
pubmed: 25624500
pmcid: 4330753
doi: 10.1073/pnas.1424927112
Hedrick, C. C. & Malanchi, I. Neutrophils in cancer: heterogeneous and multifaceted. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00571-6 (2021).
Adrover, J. M. et al. Programmed ‘disarming’ of the neutrophil proteome reduces the magnitude of inflammation. Nat. Immunol. 21, 135–144 (2020).
pubmed: 31932813
pmcid: 7223223
doi: 10.1038/s41590-019-0571-2
Grieshaber-Bouyer, R. et al. The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments. Nat. Commun. 12, 2856 (2021).
pubmed: 34001893
pmcid: 8129206
doi: 10.1038/s41467-021-22973-9
Guo, L. et al. The prognostic value of inflammation factors in hepatocellular carcinoma patients with hepatic artery interventional treatments: a retrospective study. Cancer Manag. Res. 12, 7173–7188 (2020).
pubmed: 33061563
pmcid: 7520139
doi: 10.2147/CMAR.S257934
Hu, X. G. et al. Blood neutrophil-to-lymphocyte ratio predicts tumor recurrence in patients with hepatocellular carcinoma within milan criteria after hepatectomy. Yonsei Med. J. 57, 1115–1123 (2016).
pubmed: 27401641
pmcid: 4960376
doi: 10.3349/ymj.2016.57.5.1115
Kong, W. et al. The prognostic role of a combined fibrinogen and neutrophil-to-lymphocyte ratio score in patients with resectable hepatocellular carcinoma: a retrospective study. Med. Sci. Monit. 26, e918824 (2020).
pubmed: 31929496
pmcid: 6977637
doi: 10.12659/MSM.918824
Li, X. et al. Neutrophil count is associated with myeloid derived suppressor cell level and presents prognostic value of for hepatocellular carcinoma patients. Oncotarget 8, 24380–24388 (2017).
pubmed: 28412745
pmcid: 5421855
doi: 10.18632/oncotarget.15456
Limaye, A. R. et al. Neutrophil-lymphocyte ratio predicts overall and recurrence-free survival after liver transplantation for hepatocellular carcinoma. Hepatol. Res. 43, 757–764 (2013).
pubmed: 23193965
doi: 10.1111/hepr.12019
Lu, S. D. et al. Preoperative ratio of neutrophils to lymphocytes predicts postresection survival in selected patients with early or intermediate stage hepatocellular carcinoma. Medicine 95, e2722 (2016).
pubmed: 26844516
pmcid: 4748933
doi: 10.1097/MD.0000000000002722
Margetts, J. et al. Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma? Br. J. Cancer 118, 248–257 (2018).
pubmed: 29123264
doi: 10.1038/bjc.2017.386
McVey, J. C. et al. Prognostication of inflammatory cells in liver transplantation: Is the waitlist neutrophil-to-lymphocyte ratio really predictive of tumor biology? Clin. Transpl. 33, e13743 (2019).
doi: 10.1111/ctr.13743
Okamura, Y. et al. Neutrophil to lymphocyte ratio as an indicator of the malignant behaviour of hepatocellular carcinoma. Br. J. Surg. 103, 891–898 (2016).
pubmed: 27005995
doi: 10.1002/bjs.10123
Schobert, I. T. et al. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of tumor response in hepatocellular carcinoma after DEB-TACE. Eur. Radiol. 30, 5663–5673 (2020).
pubmed: 32424595
pmcid: 7483919
doi: 10.1007/s00330-020-06931-5
Wang, Y. et al. Circulating neutrophils predict poor survival for HCC and promote HCC progression through p53 and STAT3 signaling pathway. J. Cancer 11, 3736–3744 (2020).
pubmed: 32328178
pmcid: 7171508
doi: 10.7150/jca.42953
Wu, X. L. et al. Correlation between postoperative neutrophil to lymphocyte ratio and recurrence and prognosis of hepatocellular carcinoma after radical liver resection. [in Chinese]. Zhonghua Zhong Liu Za Zhi 40, 365–371 (2018).
pubmed: 29860764
Yuan, J. et al. Peripheral blood neutrophil count as a prognostic factor for patients with hepatocellular carcinoma treated with sorafenib. Mol. Clin. Oncol. 7, 837–842 (2017).
pubmed: 29181175
pmcid: 5700259
doi: 10.3892/mco.2017.1416
Terashima, T. et al. Blood neutrophil to lymphocyte ratio as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy. Hepatol. Res. 45, 949–959 (2015).
pubmed: 25319848
doi: 10.1111/hepr.12436
Dharmapuri, S. et al. Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in advanced hepatocellular carcinoma patients treated with anti-PD-1 therapy. Cancer Med. 9, 4962–4970 (2020).
pubmed: 32419290
pmcid: 7367631
doi: 10.1002/cam4.3135
Biyik, M. et al. Blood neutrophil-to-lymphocyte ratio independently predicts survival in patients with liver cirrhosis. Eur. J. Gastroenterol. Hepatol. 25, 435–441 (2013).
pubmed: 23249602
doi: 10.1097/MEG.0b013e32835c2af3
Leithead, J. A., Rajoriya, N., Gunson, B. K. & Ferguson, J. W. Neutrophil-to-lymphocyte ratio predicts mortality in patients listed for liver transplantation. Liver Int. 35, 502–509 (2015).
pubmed: 25234369
doi: 10.1111/liv.12688
Li, S. C., Xu, Z., Deng, Y. L., Wang, Y. N. & Jia, Y. M. Higher neutrophil-lymphocyte ratio is associated with better prognosis of hepatocellular carcinoma. Medicine 99, e20919 (2020).
pubmed: 32629689
pmcid: 7337484
doi: 10.1097/MD.0000000000020919
Grenader, T. et al. Derived neutrophil lymphocyte ratio is predictive of survival from intermittent therapy in advanced colorectal cancer: a post hoc analysis of the MRC COIN study. Br. J. Cancer 114, 612–615 (2016).
pubmed: 26889974
pmcid: 4800295
doi: 10.1038/bjc.2016.23
Gu, X. et al. Prognostic significance of neutrophil-to-lymphocyte ratio in prostate cancer: evidence from 16,266 patients. Sci. Rep. 6, 22089 (2016).
pubmed: 26912340
pmcid: 4766531
doi: 10.1038/srep22089
Lin, G. et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget 7, 50963–50971 (2016).
pubmed: 26918355
pmcid: 5239451
doi: 10.18632/oncotarget.7680
Peng, B., Wang, Y. H., Liu, Y. M. & Ma, L. X. Prognostic significance of the neutrophil to lymphocyte ratio in patients with non-small cell lung cancer: a systemic review and meta-analysis. Int. J. Clin. Exp. Med. 8, 3098–3106 (2015).
pubmed: 26064198
pmcid: 4443032
Schmidt, H. et al. Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. Br. J. Cancer 93, 273–278 (2005).
pubmed: 16052222
pmcid: 2361564
doi: 10.1038/sj.bjc.6602702
Kemal, Y. et al. Elevated serum neutrophil to lymphocyte and platelet to lymphocyte ratios could be useful in lung cancer diagnosis. Asian Pac. J. Cancer Prev. 15, 2651–2654 (2014).
pubmed: 24761879
doi: 10.7314/APJCP.2014.15.6.2651
Sun, H. L. et al. Prognostic performance of lymphocyte-to-monocyte ratio in diffuse large B-cell lymphoma: an updated meta-analysis of eleven reports. Onco Targets Ther. 9, 3017–3023 (2016).
pubmed: 27284252
pmcid: 4881929
Hu, K., Lou, L., Ye, J. & Zhang, S. Prognostic role of the neutrophil-lymphocyte ratio in renal cell carcinoma: a meta-analysis. BMJ Open 5, e006404 (2015).
pubmed: 25854964
pmcid: 4390726
doi: 10.1136/bmjopen-2014-006404
Chen, W., Chen, X., Li, S. & Ren, B. Expression, immune infiltration and clinical significance of SPAG5 in hepatocellular carcinoma: a gene expression-based study. J. Gene Med. 22, e3155 (2020).
pubmed: 31860771
doi: 10.1002/jgm.3155
Gao, Q. et al. CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res. 72, 3546–3556 (2012).
pubmed: 22710437
doi: 10.1158/0008-5472.CAN-11-4032
Li, L. et al. CXCR2–CXCL1 axis is correlated with neutrophil infiltration and predicts a poor prognosis in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 34, 129 (2015).
pubmed: 26503598
pmcid: 4621872
doi: 10.1186/s13046-015-0247-1
Li, W., Xu, L., Han, J., Yuan, K. & Wu, H. Identification and validation of tumor stromal immunotype in patients with hepatocellular carcinoma. Front. Oncol. 9, 664 (2019).
pubmed: 31448222
pmcid: 6691778
doi: 10.3389/fonc.2019.00664
Li, Y. W. et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J. Hepatol. 54, 497–505 (2011).
pubmed: 21112656
doi: 10.1016/j.jhep.2010.07.044
Liu, T., Wu, H., Qi, J., Qin, C. & Zhu, Q. Seven immune-related genes prognostic power and correlation with tumor-infiltrating immune cells in hepatocellular carcinoma. Cancer Med. 9, 7440–7452 (2020).
pubmed: 32815653
pmcid: 7571821
doi: 10.1002/cam4.3406
Liu, Y. et al. Prognostic potential of PRPF3 in hepatocellular carcinoma. Aging 12, 912–930 (2020).
pubmed: 31926109
pmcid: 6977647
doi: 10.18632/aging.102665
Song, D. et al. DCK is a promising prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma. World J. Surg. Oncol. 18, 176 (2020).
pubmed: 32690026
pmcid: 7372783
doi: 10.1186/s12957-020-01953-1
Wang, Y. et al. IDO and intra-tumoral neutrophils were independent prognostic factors for overall survival for hepatocellular carcinoma. J. Clin. Lab. Anal. 33, e22872 (2019).
pubmed: 30843276
pmcid: 6595287
doi: 10.1002/jcla.22872
Zhou, S. L. et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56, 2242–2254 (2012).
pubmed: 22711685
doi: 10.1002/hep.25907
He, M. et al. Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma. Oncoimmunology 5, e1219828 (2016).
pubmed: 27853643
pmcid: 5087290
doi: 10.1080/2162402X.2016.1219828
Wu, Y. et al. Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop. J. Pathol. 225, 438–447 (2011).
pubmed: 21826665
doi: 10.1002/path.2947
Fossati, G. et al. Neutrophil infiltration into human gliomas. Acta Neuropathol. 98, 349–354 (1999).
pubmed: 10502039
doi: 10.1007/s004010051093
Ino, Y. et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br. J. Cancer 108, 914–923 (2013).
pubmed: 23385730
pmcid: 3590668
doi: 10.1038/bjc.2013.32
Jensen, H. K. et al. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J. Clin. Oncol. 27, 4709–4717 (2009).
pubmed: 19720929
doi: 10.1200/JCO.2008.18.9498
Jensen, T. O. et al. Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer 118, 2476–2485 (2012).
pubmed: 21953023
doi: 10.1002/cncr.26511
Trellakis, S. et al. Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int. J. Cancer 129, 2183–2193 (2011).
pubmed: 21190185
doi: 10.1002/ijc.25892
Zhao, J. J. et al. The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. PLoS ONE 7, e33655 (2012).
pubmed: 22442706
pmcid: 3307751
doi: 10.1371/journal.pone.0033655
Dyson, J. et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J. Hepatol. 60, 110–117 (2014).
pubmed: 23978719
doi: 10.1016/j.jhep.2013.08.011
European Assocation for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).
Eash, K. J., Greenbaum, A. M., Gopalan, P. K. & Link, D. C. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J. Clin. Invest. 120, 2423–2431 (2010).
pubmed: 20516641
pmcid: 2898597
doi: 10.1172/JCI41649
Metzemaekers, M., Gouwy, M. & Proost, P. Neutrophil chemoattractant receptors in health and disease: double-edged swords. Cell. Mol. Immunol. 17, 433–450 (2020).
pubmed: 32238918
pmcid: 7192912
doi: 10.1038/s41423-020-0412-0
Cheng, Y. et al. Cancer-associated fibroblasts induce PDL1
pubmed: 29556041
pmcid: 5859264
doi: 10.1038/s41419-018-0458-4
Chiu, D. K. et al. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C–C motif) ligand 26. Hepatology 64, 797–813 (2016).
pubmed: 27228567
doi: 10.1002/hep.28655
Mohs, A. et al. Functional role of CCL5/RANTES for HCC progression during chronic liver disease. J. Hepatol. 66, 743–753 (2017).
pubmed: 28011329
doi: 10.1016/j.jhep.2016.12.011
Xu, Y. et al. Activated hepatic stellate cells regulate MDSC migration through the SDF-1/CXCR4 axis in an orthotopic mouse model of hepatocellular carcinoma. Cancer Immunol. Immunother. 68, 1959–1969 (2019).
pubmed: 31641797
doi: 10.1007/s00262-019-02414-9
Zhang, H. et al. Tumour-activated liver stromal cells regulate myeloid-derived suppressor cells accumulation in the liver. Clin. Exp. Immunol. 188, 96–108 (2017).
pubmed: 28019655
pmcid: 5343361
doi: 10.1111/cei.12917
Haider, C. et al. Transforming growth factor-β and Axl induce CXCL5 and neutrophil recruitment in hepatocellular carcinoma. Hepatology 69, 222–236 (2019).
pubmed: 30014484
doi: 10.1002/hep.30166
Li, Y. M. et al. Receptor-interacting protein kinase 3 deficiency recruits myeloid-derived suppressor cells to hepatocellular carcinoma through the chemokine (C–X–C motif) ligand 1-chemokine (C–X–C motif) receptor 2 axis. Hepatology 70, 1564–1581 (2019).
pubmed: 31021443
doi: 10.1002/hep.30676
Liu, W. R. et al. PKM2 promotes metastasis by recruiting myeloid-derived suppressor cells and indicates poor prognosis for hepatocellular carcinoma. Oncotarget 6, 846–861 (2015).
pubmed: 25514599
doi: 10.18632/oncotarget.2749
Peng, Z. P. et al. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J. Hepatol. 73, 906–917 (2020).
pubmed: 32407813
doi: 10.1016/j.jhep.2020.05.004
Zhou, S. L. et al. A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology 70, 1214–1230 (2019).
pubmed: 30933361
doi: 10.1002/hep.30630
Wang, S. et al. S100A8/A9 in inflammation. Front. Immunol. 9, 1298 (2018).
pubmed: 29942307
pmcid: 6004386
doi: 10.3389/fimmu.2018.01298
Wilson, C. L. et al. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat. Commun. 6, 6818 (2015).
pubmed: 25879839
doi: 10.1038/ncomms7818
Wiechert, L. et al. Hepatocyte-specific S100a8 and S100a9 transgene expression in mice causes Cxcl1 induction and systemic neutrophil enrichment. Cell Commun. Signal. 10, 40 (2012).
pubmed: 23241281
pmcid: 3533587
doi: 10.1186/1478-811X-10-40
Németh, J. et al. S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis. Hepatology 50, 1251–1262 (2009).
pubmed: 19670424
doi: 10.1002/hep.23099
Liao, J. et al. High S100A9
pubmed: 34157683
pmcid: 8266308
doi: 10.18632/aging.203162
Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J. Immunol. 170, 3233–3242 (2003).
pubmed: 12626582
doi: 10.4049/jimmunol.170.6.3233
Huang, M. et al. S100A9 regulates MDSCs-mediated immune suppression via the RAGE and TLR4 signaling pathways in colorectal carcinoma. Front. Immunol. 10, 2243 (2019).
pubmed: 31620141
pmcid: 6759487
doi: 10.3389/fimmu.2019.02243
Chiu, D. K. et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat. Commun. 8, 517 (2017).
pubmed: 28894087
pmcid: 5593860
doi: 10.1038/s41467-017-00530-7
Hsieh, C. C., Hung, C. H., Chiang, M., Tsai, Y. C. & He, J. T. Hepatic stellate cells enhance liver cancer progression by inducing myeloid-derived suppressor cells through interleukin-6 signaling. Int. J. Mol. Sci. 20, 5079 (2019).
pmcid: 6834132
doi: 10.3390/ijms20205079
Xu, M. et al. Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer. Exp. Cell Res. 351, 142–149 (2017).
pubmed: 28109867
doi: 10.1016/j.yexcr.2017.01.008
Xu, Y. et al. Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2. Oncotarget 7, 8866–8878 (2016).
pubmed: 26758420
pmcid: 4891010
doi: 10.18632/oncotarget.6839
Zhou, J. et al. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut 67, 931–944 (2018).
pubmed: 28939663
doi: 10.1136/gutjnl-2017-314032
Elwan, N. et al. High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients. Immunol. Invest. 47, 169–180 (2018).
pubmed: 29182438
doi: 10.1080/08820139.2017.1407787
Shen, P., Wang, A., He, M., Wang, Q. & Zheng, S. Increased circulating Lin
pubmed: 23701406
doi: 10.1111/hepr.12167
Nourshargh, S., Renshaw, S. A. & Imhof, B. A. Reverse migration of neutrophils: where, when, how, and why? Trends Immunol. 37, 273–286 (2016).
pubmed: 27055913
doi: 10.1016/j.it.2016.03.006
Lagnado, A. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 40, e106048 (2021).
pubmed: 33764576
pmcid: 8090854
doi: 10.15252/embj.2020106048
van der Windt, D. J. et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology 68, 1347–1360 (2018).
pubmed: 29631332
doi: 10.1002/hep.29914
Wang, H. et al. Regulatory T cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J. Hepatol. 75, 1271–1283 (2021).
pubmed: 34363921
doi: 10.1016/j.jhep.2021.07.032
Yan, C., Huo, X., Wang, S., Feng, Y. & Gong, Z. Stimulation of hepatocarcinogenesis by neutrophils upon induction of oncogenic kras expression in transgenic zebrafish. J. Hepatol. 63, 420–428 (2015).
pubmed: 25828472
pmcid: 4508360
doi: 10.1016/j.jhep.2015.03.024
Chang, C. J. et al. Targeting tumor-infiltrating Ly6G
pubmed: 29266245
doi: 10.1002/ijc.31216
Hoechst, B. et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50, 799–807 (2009).
pubmed: 19551844
doi: 10.1002/hep.23054
Imai, Y. et al. Neutrophils enhance invasion activity of human cholangiocellular carcinoma and hepatocellular carcinoma cells: an in vitro study. J. Gastroenterol. Hepatol. 20, 287–293 (2005).
pubmed: 15683434
doi: 10.1111/j.1440-1746.2004.03575.x
Lacotte, S. et al. Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma. Oncoimmunology 5, e1234565 (2016).
pubmed: 27999748
pmcid: 5139644
doi: 10.1080/2162402X.2016.1234565
Li, H., Han, Y., Guo, Q., Zhang, M. & Cao, X. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-β1. J. Immunol. 182, 240–249 (2009).
pubmed: 19109155
doi: 10.4049/jimmunol.182.1.240
Li, X. F. et al. Increased autophagy sustains the survival and pro-tumorigenic effects of neutrophils in human hepatocellular carcinoma. J. Hepatol. 62, 131–139 (2015).
pubmed: 25152203
doi: 10.1016/j.jhep.2014.08.023
Yu, S. J. et al. Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J. Hepatol. 70, 449–457 (2019).
pubmed: 30414862
doi: 10.1016/j.jhep.2018.10.040
Riley, J. L. PD-1 signaling in primary T cells. Immunol. Rev. 229, 114–125 (2009).
pubmed: 19426218
pmcid: 3424066
doi: 10.1111/j.1600-065X.2009.00767.x
Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5, 641–654 (2005).
pubmed: 16056256
doi: 10.1038/nri1668
Mazzoni, A. et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 168, 689–695 (2002).
pubmed: 11777962
doi: 10.4049/jimmunol.168.2.689
Couper, K. N., Blount, D. G. & Riley, E. M. IL-10: the master regulator of immunity to infection. J. Immunol. 180, 5771–5777 (2008).
pubmed: 18424693
doi: 10.4049/jimmunol.180.9.5771
Batlle, E. & Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity 50, 924–940 (2019).
pubmed: 30995507
pmcid: 7507121
doi: 10.1016/j.immuni.2019.03.024
Yamashita, T. & Wang, X. W. Cancer stem cells in the development of liver cancer. J. Clin. Invest. 123, 1911–1918 (2013).
pubmed: 23635789
pmcid: 3635728
doi: 10.1172/JCI66024
Wang, C. Q. et al. Interleukin-6 enhances cancer stemness and promotes metastasis of hepatocellular carcinoma via up-regulating osteopontin expression. Am. J. Cancer Res. 6, 1873–1889 (2016).
pubmed: 27725896
pmcid: 5043100
Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).
pubmed: 10652271
pmcid: 316345
doi: 10.1101/gad.14.2.163
Teijeira, Á. et al. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity 52, 856–871.e858 (2020).
pubmed: 32289253
doi: 10.1016/j.immuni.2020.03.001
Feng, X. X. et al. β3 integrin promotes TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of hepatocellular carcinoma cells by enhancing TGF-β1 signaling. PLoS ONE 8, e79857 (2013).
pubmed: 24260309
pmcid: 3832483
doi: 10.1371/journal.pone.0079857
Yang, L. Y. et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J. Hematol. Oncol. 13, 3 (2020).
pubmed: 31907001
pmcid: 6945602
doi: 10.1186/s13045-019-0836-0
Gregory, A. D. & Houghton, A. M. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res. 71, 2411–2416 (2011).
pubmed: 21427354
doi: 10.1158/0008-5472.CAN-10-2583
Chee, D. O., Townsend, C. M. Jr., Galbraith, M. A., Eilber, F. R. & Morton, D. L. Selective reduction of human tumor cell populations by human granulocytes in vitro. Cancer Res. 38, 4534–4539 (1978).
pubmed: 569013
Dvorak, A. M., Connell, A. B., Proppe, K. & Dvorak, H. F. Immunologic rejection of mammary adenocarcinoma (TA3-St) in C57BL/6 mice: participation of neutrophils and activated macrophages with fibrin formation. J. Immunol. 120, 1240–1248 (1978).
pubmed: 641347
Kalafati, L. et al. Innate immune training of granulopoiesis promotes anti-tumor activity. Cell 183, 771–785.e712 (2020).
pubmed: 33125892
pmcid: 7599076
doi: 10.1016/j.cell.2020.09.058
Gershkovitz, M. et al. TRPM2 mediates neutrophil killing of disseminated tumor cells. Cancer Res. 78, 2680–2690 (2018).
pubmed: 29490946
doi: 10.1158/0008-5472.CAN-17-3614
Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).
pubmed: 25985180
pmcid: 4594765
doi: 10.1038/nature14407
Singhal, S. et al. Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 30, 120–135 (2016).
pubmed: 27374224
pmcid: 4945447
doi: 10.1016/j.ccell.2016.06.001
van Egmond, M. & Bakema, J. E. Neutrophils as effector cells for antibody-based immunotherapy of cancer. Semin. Cancer Biol. 23, 190–199 (2013).
pubmed: 23287459
doi: 10.1016/j.semcancer.2012.12.002
Matlung, H. L. et al. Neutrophils kill antibody-opsonized cancer cells by trogoptosis. Cell Rep. 23, 3946–3959.e3946 (2018).
pubmed: 29949776
doi: 10.1016/j.celrep.2018.05.082
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
pubmed: 18650514
doi: 10.1056/NEJMoa0708857
Schiffmann, L. M. et al. Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br. J. Cancer 120, 69–78 (2019).
pubmed: 30377339
doi: 10.1038/s41416-018-0198-3
Torrens, L. et al. Immunomodulatory effects of lenvatinib plus anti-PD1 in mice and rationale for patient enrichment in hepatocellular carcinoma. Hepatology 74, 2652–2669 (2021).
pubmed: 34157147
doi: 10.1002/hep.32023
Huertas, A. et al. Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma. Radiother. Oncol. 115, 211–216 (2015).
pubmed: 26028227
doi: 10.1016/j.radonc.2015.04.006
Chen, J. et al. Hypofractionated irradiation suppressed the off-target mouse hepatocarcinoma growth by inhibiting myeloid-derived suppressor cell-mediated immune suppression. Front. Oncol. 10, 4 (2020).
pubmed: 32117702
pmcid: 7026455
doi: 10.3389/fonc.2020.00004
Stadtmann, A. & Zarbock, A. CXCR2: from bench to bedside. Front. Immunol. 3, 263 (2012).
pubmed: 22936934
pmcid: 3426767
doi: 10.3389/fimmu.2012.00263
Kargl, J. et al. Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC. JCI Insight 24, e130850 (2019).
doi: 10.1172/jci.insight.130850
Weber, R. et al. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front. Immunol. 9, 1310 (2018).
pubmed: 29942309
pmcid: 6004385
doi: 10.3389/fimmu.2018.01310
Steele, C. W. et al. CXCR2 inhibition suppresses acute and chronic pancreatic inflammation. J. Pathol. 237, 85–97 (2015).
pubmed: 25950520
pmcid: 4833178
doi: 10.1002/path.4555
Jamieson, T. et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J. Clin. Invest. 122, 3127–3144 (2012).
pubmed: 22922255
pmcid: 3428079
doi: 10.1172/JCI61067
Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).
pubmed: 27265504
pmcid: 4912354
doi: 10.1016/j.ccell.2016.04.014
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02583477 (2015).
Xu, J. M. et al. Blockade of the CXCR6 signaling inhibits growth and invasion of hepatocellular carcinoma cells through inhibition of the VEGF expression. Int. J. Immunopathol. Pharmacol. 27, 553–561 (2014).
pubmed: 25572735
doi: 10.1177/039463201402700411
Peddibhotla, S. et al. Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma. Bioorg. Med. Chem. Lett. 30, 126899 (2020).
pubmed: 31882297
doi: 10.1016/j.bmcl.2019.126899
Hawila, E. et al. CCR5 directs the mobilization of CD11b
pubmed: 29166611
doi: 10.1016/j.celrep.2017.10.104
Chen, Y. et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61, 1591–1602 (2015).
pubmed: 25529917
doi: 10.1002/hep.27665
Song, J.-S. et al. A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment. Proc. Natl Acad. Sci. USA 118, e2015433118 (2021).
pubmed: 33753481
pmcid: 8020795
doi: 10.1073/pnas.2015433118
Biasci, D. et al. CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. Proc. Natl Acad. Sci. USA 117, 28960–28970 (2020).
pubmed: 33127761
pmcid: 7682333
doi: 10.1073/pnas.2013644117
Zhou, J., Nefedova, Y., Lei, A. & Gabrilovich, D. Neutrophils and PMN-MDSC: their biological role and interaction with stromal cells. Semin. Immunol. 35, 19–28 (2018).
pubmed: 29254756
doi: 10.1016/j.smim.2017.12.004
Liu, H., Shen, J. & Lu, K. IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model. Biochem. Biophys. Res. Commun. 486, 239–244 (2017).
pubmed: 28254435
doi: 10.1016/j.bbrc.2017.02.128
Fan, Y. et al. First-in-class immune-modulating small molecule icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers. BMC Cancer 19, 279 (2019).
pubmed: 30922248
pmcid: 6437929
doi: 10.1186/s12885-019-5471-1
Zhao, H. et al. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/JAK2/STAT3 pathway. Oncotarget 6, 31927–31943 (2015).
pubmed: 26376676
pmcid: 4741651
doi: 10.18632/oncotarget.5578
Zhou, J. et al. Icaritin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. Int. Immunopharmacol. 11, 890–898 (2011).
pubmed: 21244860
doi: 10.1016/j.intimp.2011.01.007
Ikeda, M. et al. A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Invest. N. Drugs 37, 118–126 (2019).
doi: 10.1007/s10637-018-0636-3
Kelley, R. K. et al. A phase 2 study of galunisertib (TGF-β1 receptor type i inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin. Transl. Gastroenterol. 10, e00056 (2019).
pubmed: 31295152
pmcid: 6708671
doi: 10.14309/ctg.0000000000000056
Radomska, H. S. et al. CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol. Cell Biol. 18, 4301–4314 (1998).
pubmed: 9632814
pmcid: 109014
doi: 10.1128/MCB.18.7.4301
Voutila, J. et al. Development and mechanism of small activating RNA targeting CEBPA, a novel therapeutic in clinical trials for liver cancer. Mol. Ther. 25, 2705–2714 (2017).
pubmed: 28882451
pmcid: 5768526
doi: 10.1016/j.ymthe.2017.07.018
Mackert, J. R. et al. Dual negative roles of C/EBPα in the expansion and pro-tumor functions of MDSCs. Sci. Rep. 7, 14048 (2017).
pubmed: 29070836
pmcid: 5656646
doi: 10.1038/s41598-017-12968-2
Reebye, V. et al. Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer. Oncogene 37, 3216–3228 (2018).
pubmed: 29511346
pmcid: 6013054
doi: 10.1038/s41388-018-0126-2
Sarker, D. et al. MTL-CEBPA, a small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label, phase I trial. Clin. Cancer Res. 26, 3936–3946 (2020).
pubmed: 32357963
doi: 10.1158/1078-0432.CCR-20-0414
Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e1386 (2015).
pubmed: 25747273
doi: 10.1053/j.gastro.2015.02.055
Yoon, J. S. et al. Adjuvant cytokine-induced killer cell immunotherapy for hepatocellular carcinoma: a propensity score-matched analysis of real-world data. BMC Cancer 19, 523 (2019).
pubmed: 31151419
pmcid: 6543598
doi: 10.1186/s12885-019-5740-z
Pilz, R. B. & Casteel, D. E. Regulation of gene expression by cyclic GMP. Circ. Res. 93, 1034–1046 (2003).
pubmed: 14645134
doi: 10.1161/01.RES.0000103311.52853.48
Rotella, D. P. Phosphodiesterase 5 inhibitors: current status and potential applications. Nat. Rev. Drug Discov. 1, 674–682 (2002).
pubmed: 12209148
doi: 10.1038/nrd893
Vellenga, E., Dokter, W. & Halie, R. M. Interleukin-4 and its receptor; modulating effects on immature and mature hematopoietic cells. Leukemia 7, 1131–1141 (1993).
pubmed: 8350614
Webb, B. L., Hirst, S. J. & Giembycz, M. A. Protein kinase C isoenzymes: a review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis. Br. J. Pharmacol. 130, 1433–1452 (2000).
pubmed: 10928943
pmcid: 1572212
doi: 10.1038/sj.bjp.0703452
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03785210 (2018).
Bitzer, M. et al. Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma — the SHELTER study. J. Hepatol. 65, 280–288 (2016).
pubmed: 26952006
doi: 10.1016/j.jhep.2016.02.043
Yeo, W. 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. 30, 3361–3367 (2012).
pubmed: 22915658
pmcid: 3438233
doi: 10.1200/JCO.2011.41.2395
Eckschlager, T., Plch, J., Stiborova, M. & Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 18, 1414 (2017).
pmcid: 5535906
doi: 10.3390/ijms18071414
Orillion, A. 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. 23, 5187–5201 (2017).
pubmed: 28698201
pmcid: 5723438
doi: 10.1158/1078-0432.CCR-17-0741
Su, Y. L., Banerjee, S., White, S. V. & Kortylewski, M. STAT3 in tumor-associated myeloid cells: multitasking to disrupt immunity. Int. J. Mol. Sci. 19, 1803 (2018).
pmcid: 6032252
doi: 10.3390/ijms19061803
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01839604 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02279719 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03195699 (2017).
Matlung, H. L., Szilagyi, K., Barclay, N. A. & van den Berg, T. K. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol. Rev. 276, 145–164 (2017).
pubmed: 28258703
doi: 10.1111/imr.12527
Lee, T. K. et al. Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60, 179–191 (2014).
pubmed: 24523067
doi: 10.1002/hep.27070
Lo, J. et al. Nuclear factor kappa B-mediated CD47 up-regulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice. Hepatology 62, 534–545 (2015).
pubmed: 25902734
doi: 10.1002/hep.27859
Xiao, Z. et al. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett. 360, 302–309 (2015).
pubmed: 25721088
pmcid: 4886734
doi: 10.1016/j.canlet.2015.02.036
Jalil, A. R., Andrechak, J. C. & Discher, D. E. Macrophage checkpoint blockade: results from initial clinical trials, binding analyses, and CD47-SIRPα structure-function. Antib. Ther. 3, 80–94 (2020).
pubmed: 32421049
pmcid: 7206415
Thorburn, A. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway signaling. J. Thorac. Oncol. 2, 461–465 (2007).
pubmed: 17545839
doi: 10.1097/JTO.0b013e31805fea64
Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014).
pubmed: 24789911
pmcid: 4038578
doi: 10.1172/JCI74056
Dominguez, G. A. et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin. Cancer Res. 23, 2942–2950 (2017).
pubmed: 27965309
doi: 10.1158/1078-0432.CCR-16-1784
Renshaw, S. A. et al. Acceleration of human neutrophil apoptosis by TRAIL. J. Immunol. 170, 1027–1033 (2003).
pubmed: 12517970
doi: 10.4049/jimmunol.170.2.1027
Cheng, A. L. 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. 63, 896–904 (2015).
pubmed: 26071796
doi: 10.1016/j.jhep.2015.06.001
Markowitz, J. & Carson, W. E. Review of S100A9 biology and its role in cancer. Biochim. Biophys. Acta 1835, 100–109 (2013).
pubmed: 23123827
Björk, P. et al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 7, e97 (2009).
pubmed: 19402754
doi: 10.1371/journal.pbio.1000097
Shen, L. et al. Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Cancer Immunol. Res. 3, 136–148 (2015).
pubmed: 25370534
doi: 10.1158/2326-6066.CIR-14-0036
Jennbacken, K. et al. Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline-3-carboxamide tasquinimod (ABR-215050). Prostate 72, 913–924 (2012).
pubmed: 22287276
doi: 10.1002/pros.21495
Deronic, A., Tahvili, S., Leanderson, T. & Ivars, F. The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth. BMC Cancer 16, 440 (2016).
pubmed: 27400708
pmcid: 4939705
doi: 10.1186/s12885-016-2481-0
Fransén Pettersson, N. et al. The immunomodulatory quinoline-3-carboxamide paquinimod reverses established fibrosis in a novel mouse model for liver fibrosis. PLoS ONE 13, e0203228 (2018).
pubmed: 30183741
pmcid: 6124744
doi: 10.1371/journal.pone.0203228
Pylaeva, E. et al. NAMPT signaling is critical for the proangiogenic activity of tumor-associated neutrophils. Int. J. Cancer 144, 136–149 (2019).
pubmed: 30121947
doi: 10.1002/ijc.31808
Shrestha, S. et al. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist attenuate tumor growth via polarization of neutrophils toward an antitumor phenotype. OncoImmunology 5, e1067744 (2016).
pubmed: 26942086
doi: 10.1080/2162402X.2015.1067744
Boivin, G. et al. Durable and controlled depletion of neutrophils in mice. Nat. Commun. 11, 2762 (2020).
pubmed: 32488020
pmcid: 7265525
doi: 10.1038/s41467-020-16596-9
Sody, S. et al. Distinct spatio-temporal dynamics of tumor-associated neutrophils in small tumor lesions. Front. Immunol. 10, 1419 (2019).
pubmed: 31293583
pmcid: 6603174
doi: 10.3389/fimmu.2019.01419
Brown, Z. J., Heinrich, B. & Greten, T. F. Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research. Nat. Rev. Gastroenterol. Hepatol. 15, 536–554 (2018).
pubmed: 29904153
doi: 10.1038/s41575-018-0033-6
Connor, F. et al. Mutational landscape of a chemically-induced mouse model of liver cancer. J. Hepatol. 69, 840–850 (2018).
pubmed: 29958939
pmcid: 6142872
doi: 10.1016/j.jhep.2018.06.009
Tian, H., Lyu, Y., Yang, Y. G. & Hu, Z. Humanized rodent models for cancer research. Front. Oncol. 10, 1696 (2020).
pubmed: 33042811
pmcid: 7518015
doi: 10.3389/fonc.2020.01696
Skelton, J. K., Ortega-Prieto, A. M. & Dorner, M. A Hitchhiker’s guide to humanized mice: new pathways to studying viral infections. Immunology 154, 50–61 (2018).
pubmed: 29446074
pmcid: 5904706
doi: 10.1111/imm.12906
Stackowicz, J., Jönsson, F. & Reber, L. L. Mouse models and tools for the in vivo study of neutrophils. Front. Immunol. 10, 3130 (2019).
pubmed: 32038641
doi: 10.3389/fimmu.2019.03130
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).
pubmed: 29967350
pmcid: 6553468
doi: 10.1038/s41591-018-0104-9
Pulli, B. et al. Myeloperoxidase-hepatocyte-stellate cell cross talk promotes hepatocyte injury and fibrosis in experimental nonalcoholic steatohepatitis. Antioxid. Redox Signal. 23, 1255–1269 (2015).
pubmed: 26058518
pmcid: 4677570
doi: 10.1089/ars.2014.6108
Harty, M. W. et al. Neutrophil depletion blocks early collagen degradation in repairing cholestatic rat livers. Am. J. Pathol. 176, 1271–1281 (2010).
pubmed: 20110408
pmcid: 2832148
doi: 10.2353/ajpath.2010.090527
Taïeb, J. et al. Polymorphonuclear neutrophils are a source of hepatocyte growth factor in patients with severe alcoholic hepatitis. J. Hepatol. 36, 342–348 (2002).
pubmed: 11867177
doi: 10.1016/S0168-8278(01)00276-8
Li, P. et al. Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status. Nat. Commun. 11, 4387 (2020).
pubmed: 32873795
pmcid: 7463263
doi: 10.1038/s41467-020-18125-0
Ogura, K. et al. NK cells control tumor-promoting function of neutrophils in mice. Cancer Immunol. Res. 6, 348–357 (2018).
pubmed: 29362222
doi: 10.1158/2326-6066.CIR-17-0204
Nejman, D. et al. The human tumor microbiome is composed of tumor type–specific intracellular bacteria. Science 368, 973–980 (2020).
pubmed: 32467386
pmcid: 7757858
doi: 10.1126/science.aay9189
Zhang, Q. et al. Gut microbiome directs hepatocytes to recruit MDSCs and promote cholangiocarcinoma. Cancer Discov. 11, 1248–1267 (2021).
pubmed: 33323397
doi: 10.1158/2159-8290.CD-20-0304
Jaillon, S. et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat. Rev. Cancer 20, 485–503 (2020).
pubmed: 32694624
doi: 10.1038/s41568-020-0281-y
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02423343 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01972672 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03236636 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03236649 (2017).
Snoderly, H. T., Boone, B. A. & Bennewitz, M. F. Neutrophil extracellular traps in breast cancer and beyond: current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment. Breast Cancer Res. 21, 145 (2019).
pubmed: 31852512
pmcid: 6921561
doi: 10.1186/s13058-019-1237-6