In the entire world, hepatocellular carcinoma (HCC) is one of the most prevalent cancers. The discovery that HCC is intimately linked to programmed cell death-1 and its ligand (PD-1/PD-L1) in recent years has opened up new possibilities for immunotherapy. However, there are no reliable biomarkers for anti-PD-1/PD-L1 immunotherapy. The latest research has found that tertiary lymphoid structures (TLS) have certain predictive value for the anti PD-1/PD-L1 immunotherapy effect of HCC.This paper analyzes the potential of TLS and PD-1/PD-L1 signaling pathway in hepatocellular carcinoma and covers the mechanism of TLS and PD-1/PD-L1 signaling route, their expression in hepatocellular carcinoma, and particular research developments in the clinic.

1.Lotfollahzadeh S, Recio-Boiles A, Babiker HM. Liver cancer[M/OL]. StatPearls. Treasure Island (FL): StatPearls Publishing, 2022. [2022-09-04]. http://www.ncbi.nlm.nih.gov/books/NBK448337/.

2.Makary MS, Khandpur U, Cloyd JM, et al. Locoregional therapy approaches for hepatocellular carcinoma: recent advances and management strategies[J]. Cancers (Basel), 2020, 12(7): 1914. DOI: 10.3390/cancers12071914.

3.Machairas N, Tsilimigras DI, Pawlik TM. State-of-the-art surgery for hepatocellular carcinoma[J]. Langenbecks Arch Surg, 2021, 406(7): 2151-2162. DOI: 10.1007/s00423-021-02298-3.

4.Chen L, Guo X, Chen S, et al. Comparison of the efficacy of pre-surgery and post-surgery radiotherapy in the treatment of hepatocellular carcinoma: a population-based study[J]. Am J Transl Res, 2021, 13(1): 360-371. https://pubmed.ncbi.nlm.nih.gov/33527030/.

5.Jiří T, Igor K, Mba. Hepatocellular carcinoma future treatment options[J]. Klin Onkol, 2020, 33(Supplementum 3): 26-29. DOI: 10.14735/amko20203S26.

6.Rodriguez De Santiago E, Téllez L, Guerrero A, et al. Hepatocellular carcinoma after fontan surgery: a systematic review[J]. Hepatol Res, 2021, 51(1): 116-134. DOI: 10.1111/hepr.13582.

7.Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications[J]. Cell Mol Immunol, 2020, 17(8): 807-821.  DOI: 10.1038/s41423-020-0488-6.

8.Zhong C, Li Y, Yang J, et al. Immunotherapy for hepatocellular carcinoma: current limits and prospects[J]. Front Oncol, 2021, 11: 589680. DOI: 10.3389/fonc.2021.589680.

9.Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors[J]. J Immunother Cancer, 2019, 7(1): 278. DOI: 10.1186/s40425-019-0768-9.

10.Barmpoutis P, Di Capite M, Kayhanian H, et al. Tertiary lymphoid structures (TLS) identification and density assessment on H&E-stained digital slides of lung cancer[J]. PLoS One, 2021, 16(9): e0256907. DOI: 10.1371/journal.pone.0256907.

11.Zhang NN, Qu FJ, Liu H, et al. Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: a systematic review and meta-analysis[J]. Cancer Cell Int, 2021, 21(1): 536. DOI: 10.1186/s12935-021-02242-x.

12.Vanhersecke L, Brunet M, Guégan JP, et al. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression[J]. Nat Cancer, 2021, 2(8): 794-802. DOI: 10.1038/s43018-021-00232-6.

13.Gao SH, Liu SZ, Wang GZ, et al. CXCL13 in cancer and other diseases: biological functions, clinical significance, and therapeutic opportunities[J]. Life (Basel), 2021, 11(12): 1282. DOI: 10.3390/life11121282.

14.Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma[J]. Nature, 2020, 577(7791): 561-565. DOI: 10.1038/s41586-019-1914-8.

15.Li K, Guo Q, Zhang X, et al. Oral cancer-associated tertiary lymphoid structures: gene expression profile and prognostic value[J]. Clin Exp Immunol, 2020, 199(2): 172-181. DOI: 10.1111/cei.13389.

16.Li Y, Tang L, Guo L, et al. CXCL13-mediated recruitment of intrahepatic CXCR5+CD8+ T cells favors viral control in chronic HBV infection[J]. J Hepatol, 2020, 72(3): 420-430. DOI: 10.1016/j.jhep.2019.09.031.

17.Li C, Kang D, Sun X, et al. The effect of C-X-C motif chemokine 13 on hepatocellular carcinoma associates with Wnt signaling[J]. Biomed Res Int, 2015, 2015: 345413. DOI: 10.1155/2015/345413.

18.Suematsu S, Watanabe T. Generation of a synthetic lymphoid tissue-like organoid in mice[J]. Nat Biotechnol, 2004, 22(12): 1539-1545. DOI: 10.1038/nbt1039.

19.Finkin S, Yuan D, Stein I, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma[J]. Nat Immunol, 2015, 16(12): 1235-1244. DOI: 10.1038/ni.3290.

20.Dieu-Nosjean MC, Giraldo NA, Kaplon H, et al. Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers[J]. Immunol Rev, 2016, 271(1): 260-275. DOI: 10.1111/imr.12405.

21.Wen S, Chen Y, Hu C, et al. Combination of tertiary lymphoid structure and neutrophil-to-lymphocyte ratio predicts survival in patients with hepatocellular carcinoma[J]. Front Immunol, 2022, 12: 788640. DOI: 10.3389/fimmu.2021.788640.

22.Nie Y, Fan H, Li J, et al. Tertiary lymphoid structures: associated multiple immune cells and analysis their formation in hepatocellular carcinoma[J]. FASEB J, 2022, 36(11): e22586. DOI: 10.1096/fj.202200269RR.

23.Murakami J, Shimizu Y, Kashii Y, et al. Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C[J]. Hepatology, 1999, 30(1): 143-150. DOI: 10.1002/hep.510300107.

24.Calderaro J, Petitprez F, Becht E, et al. Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma[J]. J Hepatol, 2019, 70(1): 58-65. DOI: 10.1016/j.jhep.2018.09.003.

25.Devi-Marulkar P, Kaplon H, Dieu-Nosjean MC, et al. Designed methods for the sorting of tertiary lymphoid structure-immune cell populations[J]. Methods Mol Biol, 2018, 1845: 189-204. DOI: 10.1007/978-1-4939-8709-2_11.

26.Zhu G, Nemoto S, Mailloux AW, et al. Induction of tertiary lymphoid structures with antitumor function by a lymph node-derived stromal cell line[J]. Front Immunol, 2018, 9: 1609. DOI: 10.3389/fimmu.2018.01609.

27.Aoyama S, Nakagawa R, Mulé JJ, et al. Inducible tertiary lymphoid structures: promise and challenges for translating a new class of immunotherapy[J]. Front Immunol, 2021, 12: 675538. DOI: 10.3389/fimmu.2021.675538.

28.Teillaud JL, Dieu-Nosjean MC. Tertiary lymphoid structures: an anti-tumor school for adaptive immune cells and an antibody factory to fight cancer?[J]. Front Immunol, 2017, 8: 830. DOI: 10.3389/fimmu.2017.00830.

29.Lin Q, Tao P, Wang J, et al. Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors[J]. Oncoimmunology, 2020, 9(1): 1747339. DOI: 10.1080/2162402X.2020.1747339.

30.Sautès-Fridman C, Petitprez F, Calderaro J, et al. Tertiary lymphoid structures in the era of cancer immunotherapy[J]. Nat Rev Cancer, 2019, 19(6): 307-325. DOI: 10.1038/s41568-019-0144-6.

31.El-Rebey HS, Abdou AG, Sultan MM, et al. The profile and role of tumor-infiltrating lymphocytes in hepatocellular carcinoma: an immunohistochemical study[J]. Applied Immunohistochemistry & Molecular Morphology: AIMM, 2021, 29(3): 188-200. DOI: 10.1097/PAI.0000000000000865.

32.Li J, Nie Y, Jia W, et al. Effect of tertiary lymphoid structures on prognosis of patients with hepatocellular carcinoma and preliminary exploration of its formation mechanism[J]. Cancers (Basel), 2022, 14(20): 5157. DOI: 10.3390/cancers14205157.

33.Li M, Sun R, Xu L, et al. Kupffer cells support hepatitis B virus-mediated CD8+ T cell exhaustion via hepatitis B core antigen-TLR2 interactions in mice[J]. J Immunol, 2015, 195(7): 3100-3109. DOI: 10.4049/jimmunol.1500839.

34.Xu L, Yin W, Sun R, et al. Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice[J]. Hepatology, 2014, 59(2): 443-452. DOI: 10.1002/hep.26668.

35.Zhao HQ. Roles of tregs in development of hepatocellular carcinoma: a meta-analysis[J]. World J Gastroenterol, 2014, 20(24): 7971-7978. DOI: 10.3748/wjg.v20.i24.7971.

36.Vaddepally RK, Kharel P, Pandey R, et al. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence[J]. Cancers (Basel), 2020, 12(3): 738. DOI: 10.3390/cancers12030738.

37.Riley JL. PD-1 signaling in primary T cells[J]. Immunol Rev, 2009, 229(1): 114-125. DOI: 10.1111/j.1600-065X.2009.00767.x.

38.Tekguc M, Wing JB, Osaki M, et al. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells[J]. Proc Natl Acad Sci U S A, 2021, 118(30): e2023739118. DOI: 10.1073/pnas.2023739118.

39.Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation[J]. Sci Signal, 2012, 5(230): ra46. DOI: 10.1126/scisignal.2002796.

40.Ghosh C, Luong G, Sun Y. A snapshot of the PD-1/PD-L1 pathway[J]. J Cancer, 2021, 12(9): 2735-2746. DOI: 10.7150/jca.57334.

41.Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer[J]. Am J Cancer Res, 2020, 10(3): 727-742. https://pubmed.ncbi.nlm.nih.gov/32266087/.

42.Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway[J]. Nat Rev Immunol, 2018, 18(3): 153-167. DOI: 10.1038/nri.2017.108.

43.Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382(20): 1894-1905. DOI: 10.1056/NEJMoa1915745.

44.Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21(4): 571-580. DOI: 10.1016/S1470-2045(20)30011-5.

45.El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502. DOI: 10.1016/S0140-6736(17)31046-2.

46.Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial[J]. J Clin Oncol, 2020, 38(3): 193-202. DOI: 10.1200/JCO.19.01307.

47.Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial[J]. Lancet Oncol, 2018, 19(7): 940-952. DOI: 10.1016/S1470-2045(18)30351-6.

48.Cai H, Zhang L, Li N, et al. Lenvatinib versus sorafenib for unresectable hepatocellular carcinoma: a cost–effectiveness analysis[J]. J Comp Eff Res, 2020, 9(8): 553-562. DOI: 10.2217/cer-2020-0041.

49.Kuzuya T, Ishigami M, Ito T, et al. Sorafenib vs. lenvatinib as first-line therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis[J]. Anticancer Res, 2020, 40(4): 2283-2290. DOI: 10.21873/anticanres.14193.

50.Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC[J]. Nature, 2021, 592(7854): 450-456. DOI: 10.1038/s41586-021-03362-0.

51.Peng Y, Wong CC, Yu J. The paradox of immunotherapy in NASH-HCC[J]. Signal Transduct Target Ther, 2021, 6(1): 228. DOI: 10.1038/s41392-021-00654-9.

52.Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types[J]. Nat Genet, 2019, 51(2): 202-206. DOI: 10.1038/s41588-018-0312-8.

53.Shrestha R, Prithviraj P, Anaka M, et al. Monitoring immune checkpoint regulators as predictive biomarkers in hepatocellular carcinoma[J]. Front Oncol, 2018, 8: 269. DOI: 10.3389/fonc.2018.00269.

54.Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study[J]. J Clin Oncol, 2017, 35(19): 2117-2124. DOI: 10.1200/JCO.2016.71.6795.

55.Chow LQM, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort[J]. Clin Oncol, 2016, 34(32): 3838-3845. DOI: 10.1200/JCO.2016.68.1478.

56.Sul J, Blumenthal GM, Jiang X, et al. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1[J]. Oncologist, 2016, 21(5): 643-650. DOI: 10.1634/theoncologist.2015-0498.

57.Yan Y, Zheng L, Du Q, et al. Interferon-γ/irf-1 pathway regulatory mechanisms of pd-l1 expression and relevance for immune checkpoint blockade in hepatocellular carcinoma (hcc)[J]. Oncotarget, 2021, 12(23): 2316. DOI: 10.18632/oncotarget.27995.

58.Fridman WH, Pagès F, Sautès-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome[J]. Nat Rev Cancer, 2012, 12(4): 298-306. DOI: 10.1038/nrc3245.

59.Sautès-Fridman C, Lawand M, Giraldo NA, et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention[J]. Front Immunol, 2016, 7: 407. DOI: 10.3389/fimmu.2016.00407.

60.Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma[J]. Nature, 2020, 577(7791): 561-565. DOI: 10.1038/s41586-019-1914-8.

61.Petitprez F, De Reyniès A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma[J]. Nature, 2020, 577(7791): 556-560. DOI: 10.1038/s41586-019-1906-8.

62.Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response[J]. Nature, 2020, 577(7791): 549-555. DOI: 10.1038/s41586-019-1922-8.

63.Clubb JHA, Kudling TV, Heiniö C, et al. Adenovirus encoding tumor necrosis factor alpha and interleukin 2 induces a tertiary lymphoid structure signature in immune checkpoint inhibitor refractory head and neck cancer[J]. Front Immunol, 2022, 13: 794251. DOI: 10.3389/fimmu.2022.794251.

64.Zhong K, Xu Y, Cheng Y, et al. Case report: primary hepatocellular carcinoma with portal vein tumor thrombus characterized by active tumor immune microenvironment achieving a complete response following treatment of combined immunotherapy[J]. Front Immunol, 2022, 13: 999763. DOI: 10.3389/fimmu.2022.999763.