#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: A meta-analysis


Autoři: Wei Ding aff001;  Yulin Tan aff001;  Yan Qian aff002;  Wenbo Xue aff001;  Yibo Wang aff001;  Peng Jiang aff001;  Xuezhong Xu aff001
Působiště autorů: Department of General Surgery, Wujin Hospital Affiliated to Jiangsu University, Changzhou, China aff001;  Department of Respiration, Changzhou Second People’s Hospital Affiliated to Nanjing Medical University, Changzhou, China aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0223971

Souhrn

Purpose

Tumor-associated macrophages (TAMs) deserve more focus because of its clinicopathologic and prognostic roles in solid tumors. However, the prognostic value of TAMs in patients with hepatocellular carcinoma (HCC) is still controversial. We performed a meta-analysis to resolve the issue.

Methods

We selected relevant studies from the Cochrane Library, Embase and PubMed databases. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials. Moreover, we also performed subgroup analysis, cumulative meta-analysis, sensitivity analysis, and bias analysis (Egger’s test).

Results

A total of 20 observational studies with 4297 patients were enrolled. For TAMs subsets, high density of CD68+ TAMs in either intratumor (IT) (pooled HR = 1.417; 95% CI = 1.092–1.839; P = 0.009) or peritumor (PT) (pooled HR = 1.393; 95% CI = 1.022–1.899; P = 0.036) was associated with a poor OS. High density of CD68+ TAMs in IT was also associated with high AFP value, large tumor size, absent encapsulation, present vascular invasion, and later tumor-nodes-metastasis (TNM) stage. High density of CD163+ macrophages in serum was associated with a poor OS (pooled HR = 5.698; 95% CI = 3.062–10.603; P < 0.001). High density of CD204+ TAMs in IT was associated with a poor OS (pooled HR = 1.947; 95% CI = 1.387–2.733; P < 0.001. High density of CD206+ TAMs in IT was associated with a poor OS (pooled HR = 1.723; 95% CI = 1.308–2.270; P < 0.001) and DFS (pooled HR = 1.711; 95% CI = 1.214–2.412; P = 0.002). However, high density of CD169+ TAMs in IT was associated with a good OS (pooled HR = 0.471; 95% CI = 0.343–0.647; P = 0.037).

Conclusions

TAMs could serve as independent predictive indicators and therapeutic targets for HCC. Further trials are needed to elucidate the exact relationship and the underlying mechanism.

Klíčová slova:

Cytokines – Cytotoxic T cells – Database searching – Hepatocellular carcinoma – China – Macrophages – Prognosis


Zdroje

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a cancer journal for clinicians. 2015;65(1):5–29. doi: 10.3322/caac.21254 25559415.

2. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nature reviews Disease primers. 2016;2:16018. doi: 10.1038/nrdp.2016.18 27158749.

3. Rasool M, Rashid S, Arooj M, Ansari SA, Khan KM, Malik A, et al. New possibilities in hepatocellular carcinoma treatment. Anticancer research. 2014;34(4):1563–71. 24692683.

4. Ginhoux F, Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity. 2016;44(3):439–49. Epub 2016/03/18. doi: 10.1016/j.immuni.2016.02.024 26982352.

5. Genard G, Lucas S, Michiels C. Reprogramming of tumor-associated macrophages with anticancer therapies: Radiotherapy versus chemo- and immunotherapies. Frontiers in Immunology. 2017;8:828. doi: 10.3389/fimmu.2017.00828 28769933

6. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nature medicine. 2013;19(11):1423–37. doi: 10.1038/nm.3394 24202395.

7. Degroote H, Van Dierendonck A, Geerts A, Van Vlierberghe H, Devisscher L. Preclinical and Clinical Therapeutic Strategies Affecting Tumor-Associated Macrophages in Hepatocellular Carcinoma. Journal of immunology research. 2018;2018:7819520. doi: 10.1155/2018/7819520 30410942.

8. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. Journal of hematology & oncology. 2017;10(1):58. doi: 10.1186/s13045-017-0430-2 28241846.

9. Ding T, Xu J, Wang F, Shi M, Zhang Y, Li SP, et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Human pathology. 2009;40(3):381–9. Epub 2008/11/11. doi: 10.1016/j.humpath.2008.08.011 18992916.

10. Li YW, Qiu SJ, Fan J, Gao Q, Zhou J, Xiao YS, et al. Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection. Journal of cancer research and clinical oncology. 2009;135(3):439–49. Epub 2008/09/11. doi: 10.1007/s00432-008-0469-0 18781326.

11. Hu H, Hang JJ, Han T, Zhuo M, Jiao F, Wang LW. The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2016;37(7):8657–64. Epub 2016/01/08. doi: 10.1007/s13277-015-4741-z 26738860.

12. Parmar MKB, Torri V, Stewart LA. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in Medicine. 1998;17(24):2815–34. doi: 10.1002/(sici)1097-0258(19981230)17:24<2815::aid-sim110>3.0.co;2-8 9921604

13. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16. Epub 2007/06/09. doi: 10.1186/1745-6215-8-16 17555582.

14. Galon J, Pages F, Marincola FM, Angell HK, Thurin M, Lugli A, et al. Cancer classification using the Immunoscore: a worldwide task force. Journal of translational medicine. 2012;10:205. Epub 2012/10/05. doi: 10.1186/1479-5876-10-205 23034130.

15. Ju MJ, Qiu SJ, Fan J, Xiao YS, Gao Q, Zhou J, et al. Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection. American journal of clinical pathology. 2009;131(4):498–510. doi: 10.1309/AJCP86PPBNGOHNNL 19289585.

16. Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. The Journal of experimental medicine. 2009;206(6):1327–37. Epub 2009/05/20. doi: 10.1084/jem.20082173 19451266.

17. Gao Q, Zhou J, Wang XY, Qiu SJ, Song K, Huang XW, et al. Infiltrating memory/senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. Annals of surgical oncology. 2012;19(2):455–66. doi: 10.1245/s10434-011-1864-3 21792513.

18. Kong LQ, Zhu XD, Xu HX, Zhang JB, Lu L, Wang WQ, et al. The clinical significance of the CD163+ and CD68+ macrophages in patients with hepatocellular carcinoma. PloS one. 2013;8(3):e59771. doi: 10.1371/journal.pone.0059771 23555776.

19. Lin SZ, Chen KJ, Xu ZY, Chen H, Zhou L, Xie HY, et al. Prediction of recurrence and survival in hepatocellular carcinoma based on two Cox models mainly determined by FoxP3+ regulatory T cells. Cancer prevention research. 2013;6(6):594–602. doi: 10.1158/1940-6207.CAPR-12-0379 23599540.

20. Waidmann O, Koberle V, Bettinger D, Trojan J, Zeuzem S, Schultheiss M, et al. Diagnostic and prognostic significance of cell death and macrophage activation markers in patients with hepatocellular carcinoma. Journal of hepatology. 2013;59(4):769–79. doi: 10.1016/j.jhep.2013.06.008 23792028.

21. Ohno A, Yorita K, Haruyama Y, Kondo K, Kato A, Ohtomo T, et al. Aberrant expression of monocarboxylate transporter 4 in tumour cells predicts an unfavourable outcome in patients with hepatocellular carcinoma. Liver international: official journal of the International Association for the Study of the Liver. 2014;34(6):942–52. doi: 10.1111/liv.12466 24433439.

22. Yeung OW, Lo CM, Ling CC, Qi X, Geng W, Li CX, et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. Journal of hepatology. 2015;62(3):607–16. doi: 10.1016/j.jhep.2014.10.029 25450711.

23. Dong P, Ma L, Liu L, Zhao G, Zhang S, Dong L, et al. CD86(+)/CD206(+), Diametrically Polarized Tumor-Associated Macrophages, Predict Hepatocellular Carcinoma Patient Prognosis. International journal of molecular sciences. 2016;17(3):320. doi: 10.3390/ijms17030320 26938527.

24. Finkelmeier F, Canli O, Tal A, Pleli T, Trojan J, Schmidt M, et al. High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis. European journal of cancer. 2016;59:152–9. doi: 10.1016/j.ejca.2016.03.002 27039170.

25. Hu ZQ, Zhou SL, Zhou ZJ, Luo CB, Chen EB, Zhan H, et al. Overexpression of semaphorin 3A promotes tumor progression and predicts poor prognosis in hepatocellular carcinoma after curative resection. Oncotarget. 2016;7(32):51733–46. Epub 2016/06/29. doi: 10.18632/oncotarget.10104 27351132.

26. Kono H, Fujii H, Furuya S, Hara M, Hirayama K, Akazawa Y, et al. Macrophage colony-stimulating factor expressed in non-cancer tissues provides predictive powers for recurrence in hepatocellular carcinoma. World journal of gastroenterology. 2016;22(39):8779–89. doi: 10.3748/wjg.v22.i39.8779 27818593.

27. Shu QH, Ge YS, Ma HX, Gao XQ, Pan JJ, Liu D, et al. Prognostic value of polarized macrophages in patients with hepatocellular carcinoma after curative resection. Journal of cellular and molecular medicine. 2016;20(6):1024–35. doi: 10.1111/jcmm.12787 26843477.

28. Zhang QB, Jia QA, Wang H, Hu CX, Sun D, Jiang RD, et al. High-mobility group protein box1 expression correlates with peritumoral macrophage infiltration and unfavorable prognosis in patients with hepatocellular carcinoma and cirrhosis. BMC cancer. 2016;16(1):880. doi: 10.1186/s12885-016-2883-z 27836008.

29. Zhang Y, Li JQ, Jiang ZZ, Li L, Wu Y, Zheng L. CD169 identifies an anti-tumour macrophage subpopulation in human hepatocellular carcinoma. The Journal of pathology. 2016;239(2):231–41. doi: 10.1002/path.4720 27174787.

30. Li JQ, Yu XJ, Wang YC, Huang LY, Liu CQ, Zheng L, et al. Distinct patterns and prognostic values of tumor-infiltrating macrophages in hepatocellular carcinoma and gastric cancer. Journal of translational medicine. 2017;15(1):37. Epub 2017/02/17. doi: 10.1186/s12967-017-1139-2 28202073.

31. Ren CX, Leng RX, Fan YG, Pan HF, Li BZ, Wu CH, et al. Intratumoral and peritumoral expression of CD68 and CD206 in hepatocellular carcinoma and their prognostic value. Oncology reports. 2017;38(2):886–98. doi: 10.3892/or.2017.5738 28656201.

32. Xie K, Xu L, Wu H, Liao H, Luo L, Liao M, et al. OX40 expression in hepatocellular carcinoma is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis. Oncoimmunology. 2018;7(4):e1404214. doi: 10.1080/2162402X.2017.1404214 29632718.

33. Chen Y, Zhang S, Wang Q, Zhang X. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. Journal of hematology & oncology. 2017;10(1):36.

34. Salmaninejad A, Valilou SF, Soltani A, Ahmadi S, Abarghan YJ, Rosengren RJ, et al. Tumor-associated macrophages: role in cancer development and therapeutic implications. Cellular oncology. 2019. doi: 10.1007/s13402-019-00453-z 31144271.

35. Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 2012;491(7423):254–8. doi: 10.1038/nature11465 23034650

36. Chanmee T, Ontong P, Konno K, Itano N. Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment. Cancers. 2014;6(3):1670–90. doi: 10.3390/cancers6031670 25125485

37. Zhang Q, Liu L, Gong C, Shi H, Zeng Y, Wang X, et al. Prognostic Significance of Tumor-Associated Macrophages in Solid Tumor: A Meta-Analysis of the Literature. PloS one. 2012;7(12).

38. Mei J, Xiao Z, Guo C, Pu Q, Ma L, Liu C, et al. Prognostic impact of tumor-associated macrophage infiltration in non-small cell lung cancer: A systemic review and meta-analysis. Oncotarget. 2016;7(23):34217–28. Epub 2016/05/05. doi: 10.18632/oncotarget.9079 27144518.

39. Troiano G, Caponio VCA, Adipietro I, Tepedino M, Santoro R, Laino L, et al. Prognostic significance of CD68(+) and CD163(+) tumor associated macrophages in head and neck squamous cell carcinoma: A systematic review and meta-analysis. Oral oncology. 2019;93:66–75. Epub 2019/05/22. doi: 10.1016/j.oraloncology.2019.04.019 31109698.

40. Yu M, Guan R, Hong W, Zhou Y, Lin Y, Jin H, et al. Prognostic value of tumor-associated macrophages in pancreatic cancer: a meta-analysis. Cancer management and research. 2019;11:4041–58. Epub 2019/05/24. doi: 10.2147/CMAR.S196951 31118813.

41. Lissbrant IF, Stattin P, Wikstrom P, Damber J, Egevad L, Bergh A. Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. International journal of oncology. 2000;17(3):445–96. doi: 10.3892/ijo.17.3.445 10938382

42. Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont AMM, Fridman WH, et al. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology. 2012;1(8):1323–43. doi: 10.4161/onci.22009 23243596

43. Kitamura T, Qian B, Pollard JW. Immune cell promotion of metastasis. Nature Reviews Immunology. 2015;15(2):73–86. doi: 10.1038/nri3789 25614318

44. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99. doi: 10.1016/j.cell.2010.01.025 20303878

45. Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity. Front Immunol. 2017;8:86. Epub 2017/02/22. doi: 10.3389/fimmu.2017.00086 28220123.

46. Martinezpomares L, Gordon S. CD169+ macrophages at the crossroads of antigen presentation. Trends in immunology. 2012;33(2):66–70. doi: 10.1016/j.it.2011.11.001 22192781

47. Grabowska J, Lopezvenegas MA, Affandi AJ, Den Haan JMM. CD169+ Macrophages Capture and Dendritic Cells Instruct: The Interplay of the Gatekeeper and the General of the Immune System. Frontiers in Immunology. 2018;9.

48. Ohnishi K, Komohara Y, Saito Y, Miyamoto Y, Watanabe M, Baba H, et al. CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma. Cancer science. 2013;104(9):1237–44. doi: 10.1111/cas.12212 23734742

49. Saito Y, Ohnishi K, Miyashita A, Nakahara S, Fujiwara Y, Horlad H, et al. Prognostic Significance of CD169+ Lymph Node Sinus Macrophages in Patients with Malignant Melanoma. Cancer immunology research. 2015;3(12):1356–63. doi: 10.1158/2326-6066.CIR-14-0180 26297710

50. Ohnishi K, Yamaguchi M, Erdenebaatar C, Saito F, Tashiro H, Katabuchi H, et al. Prognostic significance of CD169-positive lymph node sinus macrophages in patients with endometrial carcinoma. Cancer science. 2016;107(6):846–52. doi: 10.1111/cas.12929 26991548

51. Asano T, Ohnishi K, Shiota T, Motoshima T, Sugiyama Y, Yatsuda J, et al. CD169-positive sinus macrophages in the lymph nodes determine bladder cancer prognosis. Cancer science. 2018;109(5):1723–30. doi: 10.1111/cas.13565 29520898

52. Shiota T, Miyasato Y, Ohnishi K, Yamamotoibusuki M, Yamamoto Y, Iwase H, et al. The Clinical Significance of CD169-Positive Lymph Node Macrophage in Patients with Breast Cancer. PloS one. 2016;11(11).

53. Ngambenjawong C, Gustafson HH, Pun SH. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Advanced drug delivery reviews. 2017;114:206–21. Epub 2017/04/30. doi: 10.1016/j.addr.2017.04.010 28449873.

54. Wang B, Li Q, Qin L, Zhao S, Wang J, Chen X. Transition of tumor-associated macrophages from MHC class II(hi) to MHC class II(low) mediates tumor progression in mice. BMC immunology. 2011;12:43. Epub 2011/08/05. doi: 10.1186/1471-2172-12-43 21813021.

55. Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology. 2014;147(6):1393–404. Epub 2014/09/03. doi: 10.1053/j.gastro.2014.08.039 25181692.

56. Deng YR, Liu WB, Lian ZX, Li X, Hou X. Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget. 2016;7(25):38292–305. Epub 2016/10/23. doi: 10.18632/oncotarget.9438 27203677.


Článek vyšel v časopise

PLOS One


2019 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Svět praktické medicíny 1/2024 (znalostní test z časopisu)
nový kurz

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Význam metforminu pro „udržitelnou“ terapii diabetu
Autoři: prof. MUDr. Milan Kvapil, CSc., MBA

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#