Research progress on the role of tumor associated neutrophils in hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HE Linghua ,  CHEN Gang , TONG Hongxing , YANG Lei , YANG Chao , LI Sanli , LIU Kaimin

Department of Hepatobiliary Surgery, The First People’s Hospital of Kunming/The Affiliated Ganmei Hospital of Kunming Medical University, Kunming 650100, P. R. China;

Corresponding author：

CHEN Gang, Email: kmcg123@163.com

Keywords：

tumor associated neutrophil; hepatocellular carcinoma; neutrophil extracellular trap; neutrophils to lymphocytes ratio

DOI：

10.7507/1007-9424.202112012

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the important role of tumor associated neutrophils (TANs) in the occurrence, development and prognosis of hepatocellular carcinoma (HCC). Methods The basic and clinical application research literatures on the correlation between TANs and the occurrence, development and prognosis of HCC were reviewed. Results As the most abundant inflammatory cells in human body, neutrophils were also an important part of the immunosuppressive microenvironment of HCC, which was closely related to the occurrence and development, immune escape and drug sensitivity of HCC. In the tumor microenvironment, the interaction between TANs, HCC cells and other components such as neutrophil extracellular traps was regulated by a variety of signal pathways. Some parameters related to neutrophils, such as neutrophils to lymphocytes ratio, had been used as effective biomarkers for predicting the clinical prognosis of HCC patients. Conclusions The exact role of neutrophils in HCC remains to be further studied. With the continuous accumulation of research results on the function of tumor associated immunosuppressive neutrophils and new therapies targeting neutrophils, more patients with HCC will benefit from immunotherapy and personalized targeted therapy.

Citation： HE Linghua, CHEN Gang, TONG Hongxing, YANG Lei, YANG Chao, LI Sanli, LIU Kaimin. Research progress on the role of tumor associated neutrophils in hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(8): 1109-1114. doi: 10.7507/1007-9424.202112012 Copy

1.	Ilyas FZ, Beane JD, Pawlik TM. The state of immunotherapy in hepatobiliary cancers. Cells, 2021, 10(8): 2096. doi: 10.3390/cells10082096.
2.	Satilmis B, Sahin TT, Cicek E, et al. Hepatocellular carcinoma tumor microenvironment and its implications in terms of anti-tumor immunity: future perspectives for new therapeutics. J Gastrointest Cancer, 2021, 52(4): 1198-1205.
3.	Sionov RV. Leveling up the controversial role of neutrophils in cancer: when the complexity becomes entangled. Cells, 2021, 10(9): 2486. doi:10.3390/cells10092486.
4.	Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell, 2009, 16(3): 183-194.
5.	Ohms M, Möller S, Laskay T. An attempt to polarize human neutrophils toward N1 and N2 phenotypes in vitro. Front Immunol, 2020, 11: 532. doi: 10.3389/fimmu.2020.00532.
6.	Jaillon S, Ponzetta A, Di Mitri D, et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer, 2020, 20(9): 485-503.
7.	Albini A, Bruno A, Noonan DM, et al. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol, 2018, 9: 527. doi:10.3389/fimmu.2018.00527.
8.	Sionov RV, Assi S, Gershkovitz M, et al. Isolation and characterization of neutrophils with anti-tumor properties. J Vis Exp, 2015, (100): e52933. doi: 10.3791/52933.
9.	Sagiv JY, Michaeli J, Assi S, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep, 2015, 10(4): 562-573.
10.	Demkow U. Neutrophil extracellular traps (NETs) in cancer invasion, evasion and metastasis. Cancers (Basel), 2021, 13(17): 4495. doi:10.3390/cancers13174495.
11.	Qin F, Liu X, Chen J, et al. Anti-TGF-β attenuates tumor growth via polarization of tumor associated neutrophils towards an anti-tumor phenotype in colorectal cancer. J Cancer, 2020, 11(9): 2580-2592.
12.	Andzinski L, Kasnitz N, Stahnke S, et al. Type Ⅰ IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer, 2016, 138(8): 1982-1993.
13.	Korbecki J, Kojder K, Simińska D, et al. CC Chemokines in a tumor: a review of pro-cancer and anti-cancer properties of the ligands of receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci, 2020, 21(21): 8412. doi:10.3390/ijms21218412.
14.	Wu L, Saxena S, Awaji M, et al. Tumor-associated neutrophils in cancer: going pro. Cancers (Basel), 2019, 11(4): 564. doi:10.3390/cancers11040564.
15.	Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology, 2016, 150(7): 1646-1658.
16.	Song M, He J, Pan QZ, et al. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology, 2021, 73(5): 1717-1735.
17.	He M, Peng A, Huang XZ, et al. Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma. Oncoimmunology, 2016, 5(10): e1219828. doi:10.1080/2162402X.2016.1219828.
18.	Cheng Y, Li H, Deng Y, et al. Cancer-associated fibroblasts induce PDL1⁺ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis, 2018, 9(4): 422. doi:10.1038/s41419-018-0458-4.
19.	Zhou SL, Yin D, Hu ZQ, et al. A Positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology, 2019, 70(4): 1214-1230.
20.	Yan C, Yang Q, Gong Z. Tumor-associated neutrophils and macrophages promote gender disparity in hepatocellular carcinoma in zebrafish. Cancer Res, 2017, 77(6): 1395-1407.
21.	Yang Q, Yan C, Gong Z. Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish. Sci Rep, 2017, 7(1): 10315. doi:10.1038/s41598-017-10529-1.
22.	de Oliveira S, Houseright RA, Korte BG, et al. DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma. Dis Model Mech, 2020, 13(4): dmm042564. doi:10.1242/dmm.042564.
23.	Tang J, Yan Z, Feng Q, et al. The roles of neutrophils in the pathogenesis of liver diseases. Front Immunol, 2021, 12: 625472. doi:10.3389/fimmu.2021.625472.
24.	O’Rourke JM, Sagar VM, Shah T, et al. Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer. World J Gastroenterol, 2018, 24(39): 4436-4447.
25.	Calvente CJ, Tameda M, Johnson CD, et al. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223. J Clin Invest, 2019, 129(10): 4091-4109.
26.	He Y, Hwang S, Cai Y, et al. MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes. Hepatology, 2019, 70(4): 1150-1167.
27.	Gershkovitz M, Caspi Y, Fainsod-Levi T, et al. TRPM2 mediates neutrophil killing of disseminated tumor cells. Cancer Res, 2018, 78(10): 2680-2690.
28.	Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science, 2004, 303(5663): 1532-1535.
29.	Yang LY, Luo Q, Lu L, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking imorous inflammatory response. J Hematol Oncol, 2020, 13(1): 3. doi:10.1186/s13045-019-0836-0.
30.	Takesue S, Ohuchida K, Shinkawa T, et al. Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer-associated fibroblasts. Int J Oncol, 2020, 56(2): 596-605.
31.	Zenlander R, Havervall S, Magnusson M, et al. Neutrophil extracellular traps in patients with liver cirrhosis and hepatocellular carcinoma. Sci Rep, 2021, 11(1): 18025. doi:10.1038/s41598-021-97233-3.
32.	Wang H, Zhang H, Wang Y, et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J Hepatol, 2021, 75(6): 1271-1283.
33.	van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology, 2018, 68(4): 1347-1360.
34.	Xu ZG, Ye CJ, Liu LX, et al. The pretransplant neutrophil-lymphocyte ratio as a new prognostic predictor after liver transplantation for hepatocellular cancer: a systematic review and meta-analysis. Biomark Med, 2018, 12(2): 189-199.
35.	Zheng J, Cai J, Li H, et al. Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio as prognostic predictors for hepatocellular carcinoma patients with various treatments: a meta-analysis and systematic review. Cell Physiol Biochem, 2017, 44(3): 967-981.
36.	Hung HC, Lee JC, Wang YC, et al. Response prediction in immune checkpoint inhibitor immunotherapy for advanced hepatocellular carcinoma. Cancers (Basel), 2021, 13(7): 1607. doi:10.3390/cancers13071607.
37.	Eso Y, Takeda H, Taura K, et al. Pretreatment neutrophil-to-lymphocyte ratio as a predictive marker of response to atezolizumab plus bevacizumab for hepatocellular carcinoma. Curr Oncol, 2021, 28(5): 4157-4166.
38.	朱心睿, 张晓赟, 彭伟, 等. 中性粒细胞/淋巴细胞比值对接受经肝动脉化疗栓塞+甲磺酸仑伐替尼+卡瑞利珠单抗治疗的不可切除肝癌的预后预测意义. 中国普外基础与临床杂志, 2021, 28(11): 1426-1433.
39.	Colotta F, Re F, Polentarutti N, et al. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood, 1992, 80(8): 2012-2020.
40.	van Raam BJ, Drewniak A, Groenewold V, et al. Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3. Blood, 2008, 112(5): 2046-2054.
41.	Hajizadeh F, Aghebati Maleki L, Alexander M, et al. Tumor-associated neutrophils as new players in immunosuppressive process of the tumor microenvironment in breast cancer. Life Sci, 2021, 264: 118699. doi:10.1016/j.lfs.2020.118699.
42.	Sawanobori Y, Ueha S, Kurachi M, et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood, 2008, 111(12): 5457-5466.
43.	Guisier F, Barros-Filho MC, Rock LD, et al. Janus or Hydra: the many faces of t helper cells in the human tumour microenvironment. Adv Exp Med Biol, 2020, 1224: 35-51.
44.	Barnes TA, Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer, 2018, 118(2): e5. doi:10.1038/bjc.2017.417.
45.	Min GT, Li YM, Yao N, et al. The pretreatment neutrophil-lymphocyte ratio may predict prognosis of patients with liver cancer: A systematic review and meta-analysis. Clin Transplant, 2018, 32(1) : 10.1111/ctr. 13151. doi:10.1111/ctr.13151.
46.	Mouchli M, Reddy S, Gerrard M, et al. Usefulness of neutrophil-to-lymphocyte ratio (NLR) as a prognostic predictor after treatment of hepatocellular carcinoma. Review article. Ann Hepatol, 2021, 22: 100249. doi:10.1016/j.aohep.2020.08.067.

1. Ilyas FZ, Beane JD, Pawlik TM. The state of immunotherapy in hepatobiliary cancers. Cells, 2021, 10(8): 2096. doi: 10.3390/cells10082096.
2. Satilmis B, Sahin TT, Cicek E, et al. Hepatocellular carcinoma tumor microenvironment and its implications in terms of anti-tumor immunity: future perspectives for new therapeutics. J Gastrointest Cancer, 2021, 52(4): 1198-1205.
3. Sionov RV. Leveling up the controversial role of neutrophils in cancer: when the complexity becomes entangled. Cells, 2021, 10(9): 2486. doi:10.3390/cells10092486.
4. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell, 2009, 16(3): 183-194.
5. Ohms M, Möller S, Laskay T. An attempt to polarize human neutrophils toward N1 and N2 phenotypes in vitro. Front Immunol, 2020, 11: 532. doi: 10.3389/fimmu.2020.00532.
6. Jaillon S, Ponzetta A, Di Mitri D, et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer, 2020, 20(9): 485-503.
7. Albini A, Bruno A, Noonan DM, et al. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol, 2018, 9: 527. doi:10.3389/fimmu.2018.00527.
8. Sionov RV, Assi S, Gershkovitz M, et al. Isolation and characterization of neutrophils with anti-tumor properties. J Vis Exp, 2015, (100): e52933. doi: 10.3791/52933.
9. Sagiv JY, Michaeli J, Assi S, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep, 2015, 10(4): 562-573.
10. Demkow U. Neutrophil extracellular traps (NETs) in cancer invasion, evasion and metastasis. Cancers (Basel), 2021, 13(17): 4495. doi:10.3390/cancers13174495.
11. Qin F, Liu X, Chen J, et al. Anti-TGF-β attenuates tumor growth via polarization of tumor associated neutrophils towards an anti-tumor phenotype in colorectal cancer. J Cancer, 2020, 11(9): 2580-2592.
12. Andzinski L, Kasnitz N, Stahnke S, et al. Type Ⅰ IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer, 2016, 138(8): 1982-1993.
13. Korbecki J, Kojder K, Simińska D, et al. CC Chemokines in a tumor: a review of pro-cancer and anti-cancer properties of the ligands of receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci, 2020, 21(21): 8412. doi:10.3390/ijms21218412.
14. Wu L, Saxena S, Awaji M, et al. Tumor-associated neutrophils in cancer: going pro. Cancers (Basel), 2019, 11(4): 564. doi:10.3390/cancers11040564.
15. Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology, 2016, 150(7): 1646-1658.
16. Song M, He J, Pan QZ, et al. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology, 2021, 73(5): 1717-1735.
17. He M, Peng A, Huang XZ, et al. Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma. Oncoimmunology, 2016, 5(10): e1219828. doi:10.1080/2162402X.2016.1219828.
18. Cheng Y, Li H, Deng Y, et al. Cancer-associated fibroblasts induce PDL1⁺ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis, 2018, 9(4): 422. doi:10.1038/s41419-018-0458-4.
19. Zhou SL, Yin D, Hu ZQ, et al. A Positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology, 2019, 70(4): 1214-1230.
20. Yan C, Yang Q, Gong Z. Tumor-associated neutrophils and macrophages promote gender disparity in hepatocellular carcinoma in zebrafish. Cancer Res, 2017, 77(6): 1395-1407.
21. Yang Q, Yan C, Gong Z. Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish. Sci Rep, 2017, 7(1): 10315. doi:10.1038/s41598-017-10529-1.
22. de Oliveira S, Houseright RA, Korte BG, et al. DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma. Dis Model Mech, 2020, 13(4): dmm042564. doi:10.1242/dmm.042564.
23. Tang J, Yan Z, Feng Q, et al. The roles of neutrophils in the pathogenesis of liver diseases. Front Immunol, 2021, 12: 625472. doi:10.3389/fimmu.2021.625472.
24. O’Rourke JM, Sagar VM, Shah T, et al. Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer. World J Gastroenterol, 2018, 24(39): 4436-4447.
25. Calvente CJ, Tameda M, Johnson CD, et al. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223. J Clin Invest, 2019, 129(10): 4091-4109.
26. He Y, Hwang S, Cai Y, et al. MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes. Hepatology, 2019, 70(4): 1150-1167.
27. Gershkovitz M, Caspi Y, Fainsod-Levi T, et al. TRPM2 mediates neutrophil killing of disseminated tumor cells. Cancer Res, 2018, 78(10): 2680-2690.
28. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science, 2004, 303(5663): 1532-1535.
29. Yang LY, Luo Q, Lu L, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking imorous inflammatory response. J Hematol Oncol, 2020, 13(1): 3. doi:10.1186/s13045-019-0836-0.
30. Takesue S, Ohuchida K, Shinkawa T, et al. Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer-associated fibroblasts. Int J Oncol, 2020, 56(2): 596-605.
31. Zenlander R, Havervall S, Magnusson M, et al. Neutrophil extracellular traps in patients with liver cirrhosis and hepatocellular carcinoma. Sci Rep, 2021, 11(1): 18025. doi:10.1038/s41598-021-97233-3.
32. Wang H, Zhang H, Wang Y, et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J Hepatol, 2021, 75(6): 1271-1283.
33. van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology, 2018, 68(4): 1347-1360.
34. Xu ZG, Ye CJ, Liu LX, et al. The pretransplant neutrophil-lymphocyte ratio as a new prognostic predictor after liver transplantation for hepatocellular cancer: a systematic review and meta-analysis. Biomark Med, 2018, 12(2): 189-199.
35. Zheng J, Cai J, Li H, et al. Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio as prognostic predictors for hepatocellular carcinoma patients with various treatments: a meta-analysis and systematic review. Cell Physiol Biochem, 2017, 44(3): 967-981.
36. Hung HC, Lee JC, Wang YC, et al. Response prediction in immune checkpoint inhibitor immunotherapy for advanced hepatocellular carcinoma. Cancers (Basel), 2021, 13(7): 1607. doi:10.3390/cancers13071607.
37. Eso Y, Takeda H, Taura K, et al. Pretreatment neutrophil-to-lymphocyte ratio as a predictive marker of response to atezolizumab plus bevacizumab for hepatocellular carcinoma. Curr Oncol, 2021, 28(5): 4157-4166.
38. 朱心睿, 张晓赟, 彭伟, 等. 中性粒细胞/淋巴细胞比值对接受经肝动脉化疗栓塞+甲磺酸仑伐替尼+卡瑞利珠单抗治疗的不可切除肝癌的预后预测意义. 中国普外基础与临床杂志, 2021, 28(11): 1426-1433.
39. Colotta F, Re F, Polentarutti N, et al. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood, 1992, 80(8): 2012-2020.
40. van Raam BJ, Drewniak A, Groenewold V, et al. Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3. Blood, 2008, 112(5): 2046-2054.
41. Hajizadeh F, Aghebati Maleki L, Alexander M, et al. Tumor-associated neutrophils as new players in immunosuppressive process of the tumor microenvironment in breast cancer. Life Sci, 2021, 264: 118699. doi:10.1016/j.lfs.2020.118699.
42. Sawanobori Y, Ueha S, Kurachi M, et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood, 2008, 111(12): 5457-5466.
43. Guisier F, Barros-Filho MC, Rock LD, et al. Janus or Hydra: the many faces of t helper cells in the human tumour microenvironment. Adv Exp Med Biol, 2020, 1224: 35-51.
44. Barnes TA, Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer, 2018, 118(2): e5. doi:10.1038/bjc.2017.417.
45. Min GT, Li YM, Yao N, et al. The pretreatment neutrophil-lymphocyte ratio may predict prognosis of patients with liver cancer: A systematic review and meta-analysis. Clin Transplant, 2018, 32(1) : 10.1111/ctr. 13151. doi:10.1111/ctr.13151.
46. Mouchli M, Reddy S, Gerrard M, et al. Usefulness of neutrophil-to-lymphocyte ratio (NLR) as a prognostic predictor after treatment of hepatocellular carcinoma. Review article. Ann Hepatol, 2021, 22: 100249. doi:10.1016/j.aohep.2020.08.067.

Previous Article
Research progress on relation between dietary factors and risk of pancreatic cancer
Next Article
Research progress in nonalcoholic fatty liver disease: disease burden and medical expenses control

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress on the role of tumor associated neutrophils in hepatocellular carcinoma

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content