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  • Review Article
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Neutrophils as potential therapeutic targets in hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 19, pages 257–273 (2022)Cite this article

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Abstract

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.

Key points

  • A growing body of evidence identifies neutrophils as central to the pathogenesis of hepatocellular carcinoma (HCC) and as having important roles in tumorigenesis, local tumour progression and metastasis.

  • The main mechanisms by which neutrophils drive tumour progression are immunosuppression, direct enhancement of tumour cell survival, invasiveness and metastatic capacity, extracellular matrix remodelling and angiogenesis.

  • Single-cell technologies show that neutrophils probably have a dynamic spectrum of pro-tumour and antitumour functions that vary according to their microenvironment; as such, the current phenotypic classification should be revisited.

  • Preclinical studies demonstrate that targeting neutrophils is an effective strategy in HCC: therapies that selectively target tumour-promoting neutrophil functions, signalling pathways and chemotaxis are currently under investigation.

  • Manipulation of neutrophil function could potentially render the HCC immune microenvironment more permissive to systemic immunotherapies.

  • Further work, including improvements in preclinical models and single-cell technologies, is needed to determine the phenotypes of neutrophils in HCC and in chronic liver diseases.

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Fig. 1: Neutrophil tumour recruitment and polarization in hepatocellular carcinoma.
Fig. 2: Neutrophil-driven tumour-promoting mechanisms in hepatocellular carcinoma.
Fig. 3: Promising neutrophil-directed therapeutic targets in hepatocellular carcinoma.

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References

  1. 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).

    Article  PubMed  Google Scholar 

  2. Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450–1462 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 7, 6 (2021).

    Article  PubMed  Google Scholar 

  4. 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).

  5. Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Borregaard, N. Neutrophils, from marrow to microbes. Immunity 33, 657–670 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Li, Y. et al. The regulatory roles of neutrophils in adaptive immunity. Cell Commun. Signal. 17, 147 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rosales, C. Neutrophil: a cell with many roles in inflammation or several cell types? Front. Physiol. 9, 113 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Liu, K., Wang, F.-S. & Xu, R. Neutrophils in liver diseases: pathogenesis and therapeutic targets. Cell. Mol. Immunol. 18, 38–44 (2021).

    Article  CAS  PubMed  Google Scholar 

  10. Brostjan, C. & Oehler, R. The role of neutrophil death in chronic inflammation and cancer. Cell Death Discov. 6, 26 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. Ballesteros, I. et al. Co-option of neutrophil fates by tissue environments. Cell 183, 1282–1297.e1 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Shaul, M. E. & Fridlender, Z. G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 16, 601–620 (2019).

    Article  PubMed  Google Scholar 

  15. Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Blattner, C. et al. CCR5+ myeloid-derived suppressor cells are enriched and activated in melanoma lesions. Cancer Res. 78, 157–167 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. Munder, M. et al. Suppression of T-cell functions by human granulocyte arginase. Blood 108, 1627–1634 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rice, C. M. et al. Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression. Nat. Commun. 9, 5099 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kusmartsev, S., Nefedova, Y., Yoder, D. & Gabrilovich, D. I. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172, 989–999 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  PubMed  Google Scholar 

  42. 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).

  43. Schoof, E. M. et al. Quantitative single-cell proteomics as a tool to characterize cellular hierarchies. Nat. Commun. 12, 3341 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lang, S. et al. Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin. Cancer Res. 24, 4834–4844 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Liu, C. Y. et al. Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14–/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J. Cancer Res. Clin. Oncol. 136, 35–45 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. Veglia, F. et al. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 569, 73–78 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mackey, J. B. G., Coffelt, S. B. & Carlin, L. M. Neutrophil maturity in cancer. Front. Immunol. 10, 1912 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hedrick, C. C. & Malanchi, I. Neutrophils in cancer: heterogeneous and multifaceted. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00571-6 (2021).

  54. Adrover, J. M. et al. Programmed ‘disarming’ of the neutrophil proteome reduces the magnitude of inflammation. Nat. Immunol. 21, 135–144 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Grieshaber-Bouyer, R. et al. The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments. Nat. Commun. 12, 2856 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Margetts, J. et al. Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma? Br. J. Cancer 118, 248–257 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gu, X. et al. Prognostic significance of neutrophil-to-lymphocyte ratio in prostate cancer: evidence from 16,266 patients. Sci. Rep. 6, 22089 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 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  PubMed Central  Google Scholar 

  78. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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).

    Article  PubMed  Google Scholar 

  80. 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  PubMed Central  Google Scholar 

  81. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  82. 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).

    Article  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  Google Scholar 

  84. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  85. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Li, Y. W. et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J. Hepatol. 54, 497–505 (2011).

    Article  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu, Y. et al. Prognostic potential of PRPF3 in hepatocellular carcinoma. Aging 12, 912–930 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  90. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Zhou, S. L. et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56, 2242–2254 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. He, M. et al. Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma. Oncoimmunology 5, e1219828 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wu, Y. et al. Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop. J. Pathol. 225, 438–447 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Fossati, G. et al. Neutrophil infiltration into human gliomas. Acta Neuropathol. 98, 349–354 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Ino, Y. et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br. J. Cancer 108, 914–923 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    Article  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  99. Zhao, J. J. et al. The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. PLoS ONE 7, e33655 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dyson, J. et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J. Hepatol. 60, 110–117 (2014).

    Article  PubMed  Google Scholar 

  101. European Assocation for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).

  102. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Metzemaekers, M., Gouwy, M. & Proost, P. Neutrophil chemoattractant receptors in health and disease: double-edged swords. Cell. Mol. Immunol. 17, 433–450 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Cheng, Y. et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 9, 422 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  105. 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).

    Article  CAS  PubMed  Google Scholar 

  106. Mohs, A. et al. Functional role of CCL5/RANTES for HCC progression during chronic liver disease. J. Hepatol. 66, 743–753 (2017).

    Article  CAS  PubMed  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Haider, C. et al. Transforming growth factor-β and Axl induce CXCL5 and neutrophil recruitment in hepatocellular carcinoma. Hepatology 69, 222–236 (2019).

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  PubMed  Google Scholar 

  112. 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).

    Article  CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. Wang, S. et al. S100A8/A9 in inflammation. Front. Immunol. 9, 1298 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wilson, C. L. et al. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat. Commun. 6, 6818 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    Article  PubMed  Google Scholar 

  118. Liao, J. et al. High S100A9+ cell density predicts a poor prognosis in hepatocellular carcinoma patients after curative resection. Aging 13, 16367–16380 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 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).

    Article  CAS  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  CAS  PubMed Central  Google Scholar 

  123. 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).

    Article  CAS  PubMed  Google Scholar 

  124. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  125. 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).

    Article  CAS  PubMed  Google Scholar 

  126. 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).

    Article  CAS  PubMed  Google Scholar 

  127. Shen, P., Wang, A., He, M., Wang, Q. & Zheng, S. Increased circulating Lin–/low CD33+ HLA-DR– myeloid-derived suppressor cells in hepatocellular carcinoma patients. Hepatol. Res. 44, 639–650 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. Nourshargh, S., Renshaw, S. A. & Imhof, B. A. Reverse migration of neutrophils: where, when, how, and why? Trends Immunol. 37, 273–286 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Lagnado, A. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 40, e106048 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 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).

    Article  PubMed  Google Scholar 

  131. 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).

    Article  CAS  PubMed  Google Scholar 

  132. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Chang, C. J. et al. Targeting tumor-infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma. Int. J. Cancer 142, 1878–1889 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. 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).

    Article  CAS  PubMed  Google Scholar 

  135. 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).

    Article  CAS  PubMed  Google Scholar 

  136. Lacotte, S. et al. Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma. Oncoimmunology 5, e1234565 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  137. 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).

    Article  CAS  PubMed  Google Scholar 

  138. 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).

    Article  CAS  PubMed  Google Scholar 

  139. 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).

    Article  CAS  PubMed  Google Scholar 

  140. Riley, J. L. PD-1 signaling in primary T cells. Immunol. Rev. 229, 114–125 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Bronte, V. & Zanovello, P. Regulation of immune responses by l-arginine metabolism. Nat. Rev. Immunol. 5, 641–654 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Mazzoni, A. et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 168, 689–695 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Couper, K. N., Blount, D. G. & Riley, E. M. IL-10: the master regulator of immunity to infection. J. Immunol. 180, 5771–5777 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Batlle, E. & Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity 50, 924–940 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Yamashita, T. & Wang, X. W. Cancer stem cells in the development of liver cancer. J. Clin. Invest. 123, 1911–1918 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  148. 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).

    Article  CAS  PubMed  Google Scholar 

  149. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  150. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gregory, A. D. & Houghton, A. M. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res. 71, 2411–2416 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. 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).

    CAS  PubMed  Google Scholar 

  153. 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).

    CAS  PubMed  Google Scholar 

  154. Kalafati, L. et al. Innate immune training of granulopoiesis promotes anti-tumor activity. Cell 183, 771–785.e712 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Gershkovitz, M. et al. TRPM2 mediates neutrophil killing of disseminated tumor cells. Cancer Res. 78, 2680–2690 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. van Egmond, M. & Bakema, J. E. Neutrophils as effector cells for antibody-based immunotherapy of cancer. Semin. Cancer Biol. 23, 190–199 (2013).

    Article  PubMed  Google Scholar 

  159. Matlung, H. L. et al. Neutrophils kill antibody-opsonized cancer cells by trogoptosis. Cell Rep. 23, 3946–3959.e3946 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  161. Schiffmann, L. M. et al. Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br. J. Cancer 120, 69–78 (2019).

    Article  CAS  PubMed  Google Scholar 

  162. 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).

    Article  CAS  PubMed  Google Scholar 

  163. Huertas, A. et al. Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma. Radiother. Oncol. 115, 211–216 (2015).

    Article  PubMed  Google Scholar 

  164. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Stadtmann, A. & Zarbock, A. CXCR2: from bench to bedside. Front. Immunol. 3, 263 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Kargl, J. et al. Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC. JCI Insight 24, e130850 (2019).

    Article  Google Scholar 

  167. Weber, R. et al. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front. Immunol. 9, 1310 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Steele, C. W. et al. CXCR2 inhibition suppresses acute and chronic pancreatic inflammation. J. Pathol. 237, 85–97 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Jamieson, T. et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J. Clin. Invest. 122, 3127–3144 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02583477 (2015).

  172. 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).

    Article  CAS  PubMed  Google Scholar 

  173. 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).

    Article  CAS  PubMed  Google Scholar 

  174. Hawila, E. et al. CCR5 directs the mobilization of CD11b+Gr1+Ly6Clow polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep. 21, 2212–2222 (2017).

    Article  CAS  PubMed  Google Scholar 

  175. 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).

    Article  CAS  PubMed  Google Scholar 

  176. Song, J.-S. et al. A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment. Proc. Natl Acad. Sci. USA 118, e2015433118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 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).

    Article  CAS  PubMed  Google Scholar 

  179. 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).

    Article  CAS  PubMed  Google Scholar 

  180. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  181. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  182. 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).

    Article  CAS  PubMed  Google Scholar 

  183. 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).

    Article  CAS  Google Scholar 

  184. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  188. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 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).

    Article  CAS  PubMed  Google Scholar 

  190. Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e1386 (2015).

    Article  CAS  PubMed  Google Scholar 

  191. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Pilz, R. B. & Casteel, D. E. Regulation of gene expression by cyclic GMP. Circ. Res. 93, 1034–1046 (2003).

    Article  CAS  PubMed  Google Scholar 

  193. Rotella, D. P. Phosphodiesterase 5 inhibitors: current status and potential applications. Nat. Rev. Drug Discov. 1, 674–682 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. 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).

    CAS  PubMed  Google Scholar 

  195. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03785210 (2018).

  197. Bitzer, M. et al. Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma — the SHELTER study. J. Hepatol. 65, 280–288 (2016).

    Article  CAS  PubMed  Google Scholar 

  198. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Eckschlager, T., Plch, J., Stiborova, M. & Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 18, 1414 (2017).

    Article  PubMed Central  Google Scholar 

  200. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. 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).

    Article  PubMed Central  Google Scholar 

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01839604 (2017).

  203. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02279719 (2014).

  204. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03195699 (2017).

  205. 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).

    Article  CAS  PubMed  Google Scholar 

  206. 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).

    Article  CAS  PubMed  Google Scholar 

  207. 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).

    Article  CAS  PubMed  Google Scholar 

  208. Xiao, Z. et al. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett. 360, 302–309 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Thorburn, A. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway signaling. J. Thorac. Oncol. 2, 461–465 (2007).

    Article  PubMed  Google Scholar 

  211. Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. 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).

    Article  CAS  PubMed  Google Scholar 

  213. Renshaw, S. A. et al. Acceleration of human neutrophil apoptosis by TRAIL. J. Immunol. 170, 1027–1033 (2003).

    Article  CAS  PubMed  Google Scholar 

  214. 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).

    Article  CAS  PubMed  Google Scholar 

  215. Markowitz, J. & Carson, W. E. Review of S100A9 biology and its role in cancer. Biochim. Biophys. Acta 1835, 100–109 (2013).

    CAS  PubMed  Google Scholar 

  216. 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).

    Article  PubMed  Google Scholar 

  217. Shen, L. et al. Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Cancer Immunol. Res. 3, 136–148 (2015).

    Article  CAS  PubMed  Google Scholar 

  218. 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).

    Article  CAS  PubMed  Google Scholar 

  219. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  220. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Pylaeva, E. et al. NAMPT signaling is critical for the proangiogenic activity of tumor-associated neutrophils. Int. J. Cancer 144, 136–149 (2019).

    Article  CAS  PubMed  Google Scholar 

  222. 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).

    Article  PubMed  Google Scholar 

  223. Boivin, G. et al. Durable and controlled depletion of neutrophils in mice. Nat. Commun. 11, 2762 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Sody, S. et al. Distinct spatio-temporal dynamics of tumor-associated neutrophils in small tumor lesions. Front. Immunol. 10, 1419 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. 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).

    Article  CAS  PubMed  Google Scholar 

  226. Connor, F. et al. Mutational landscape of a chemically-induced mouse model of liver cancer. J. Hepatol. 69, 840–850 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Tian, H., Lyu, Y., Yang, Y. G. & Hu, Z. Humanized rodent models for cancer research. Front. Oncol. 10, 1696 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  228. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Stackowicz, J., Jönsson, F. & Reber, L. L. Mouse models and tools for the in vivo study of neutrophils. Front. Immunol. 10, 3130 (2019).

    Article  CAS  PubMed  Google Scholar 

  230. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Harty, M. W. et al. Neutrophil depletion blocks early collagen degradation in repairing cholestatic rat livers. Am. J. Pathol. 176, 1271–1281 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. 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).

    Article  PubMed  Google Scholar 

  234. Li, P. et al. Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status. Nat. Commun. 11, 4387 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Ogura, K. et al. NK cells control tumor-promoting function of neutrophils in mice. Cancer Immunol. Res. 6, 348–357 (2018).

    Article  CAS  PubMed  Google Scholar 

  236. Nejman, D. et al. The human tumor microbiome is composed of tumor type–specific intracellular bacteria. Science 368, 973–980 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Zhang, Q. et al. Gut microbiome directs hepatocytes to recruit MDSCs and promote cholangiocarcinoma. Cancer Discov. 11, 1248–1267 (2021).

    Article  CAS  PubMed  Google Scholar 

  238. Jaillon, S. et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat. Rev. Cancer 20, 485–503 (2020).

    Article  CAS  PubMed  Google Scholar 

  239. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02423343 (2015).

  240. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01972672 (2013).

  241. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03236636 (2017).

  242. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03236649 (2017).

  243. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

D.G. is funded by the Newcastle Cancer Research UK (CRUK) Clinical Academic Training Programme. T.G.B. is funded by the Wellcome Trust (grant WT107492Z). D.A.M. received grant funding from the UK Medical Research Council (MRC) (grants MR/K0019494/1 and MR/R023026/1). J.L., D.A.M. and H.L.R. received grant funding from CRUK (grant C18342/A23390). T.G.B., D.A.M. and H.L.R. received funding from the CRUK Hepatocellular Carcinoma Expediter Network (HUNTER) Accelerator Award (A26813).

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Authors and Affiliations

  1. Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Daniel Geh, Jack Leslie & Derek A. Mann

  2. School of Pharmacy, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Rob Rumney

  3. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Helen L. Reeves

  4. The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK

    Helen L. Reeves

  5. Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK

    Helen L. Reeves

  6. Cancer Research UK Beatson Institute, Glasgow, UK

    Thomas G. Bird

  7. MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK

    Thomas G. Bird

  8. Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey

    Derek A. Mann

Authors
  1. Daniel Geh
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  2. Jack Leslie
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  3. Rob Rumney
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  4. Helen L. Reeves
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  5. Thomas G. Bird
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  6. Derek A. Mann
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Contributions

D.G., T.G.B., and D.A.M. contributed to all aspects of the article. J.L. and H.L.R. contributed substantially to discussions of the content, writing and review or editing of the manuscript before submission. R.R. researched data for the article and wrote the manuscript.

Corresponding author

Correspondence to Derek A. Mann.

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The authors declare no competing interests.

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Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Allan Tsung, who co-reviewed with Hai Huang; Tim Greten; and Limin Zheng for their contribution to the peer review of this work.

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Supplementary information

Glossary

Neutrophil extracellular traps

(NETs). Extracellular web-like structures released by activated neutrophils, made up of a network of chromatin and granule proteins such as neutrophil elastase and myeloperoxidase; NETs have a variety of antimicrobial and immune-modulating functions.

Tumour-associated neutrophils

(TANs). The neutrophils found within or around a tumour.

Reactive oxygen species

(ROS). Unstable molecules containing oxygen free radicals (such as hydrogen peroxide and superoxides) that readily react with other molecules; stimulated neutrophils generate ROS by activating the NADPH oxidase complex, which is one of their main antimicrobial mechanisms.

Stelic animal model

(STAM). In STAM mice, hepatocellular carcinoma (HCC) develops on the background of streptozotocin-induced type 1 diabetes mellitus and steatosis induced by a high-fat diet, which mimics the development of HCC on the background of nonalcoholic steatohepatitis.

Trogoptosis

A mechanism by which neutrophils exert antibody-dependent cellular cytotoxicity (ADCC) towards tumour cells; trogoptosis is restricted by CD47–SIRPα interactions and involves trogocytosis, which activates neutrophil degranulation and cytotoxicity.

Heterotopic model

The implantation of tumour cells into organs or tissues of an animal that do not match the tumour cells’ organ or tissues of origin.

Orthotopic model

The implantation of tumour cells into the organ or tissues of an animal that match the tumour cells organ or tissues of origin.

Syngeneic

Cells with an identical genetic background, which are immunologically compatible and therefore can be transplanted into another organism without eliciting an immune response.

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Geh, D., Leslie, J., Rumney, R. et al. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 19, 257–273 (2022). https://doi.org/10.1038/s41575-021-00568-5

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