Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Jul 18

PMID 35844587

Authors

Weili Jia

Tianchen Zhang

Qianyun Yao

Jianhui Li

Ye Nie

Xinjun Lei

Zhenzhen Mao

Yanfang Wang

Wen Shi

Wenjie Song

Affiliations

Soon will be listed here.

Abstract

Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells found in the tumor microenvironment. TLS can influence primary hepatic carcinoma (PHC) occurrence and have an active role in cancer. TLS can promote or inhibit the growth of PHC depending on their location, and although available findings are controversial, they suggest that TLS have a protective role in PHC tissues and a non-protective role in paracancerous tissues. In addition, the cellular composition of TLS can also influence the outcome of PHC. As an immunity marker, TLS can act as a marker of immunotherapy to predict its effect and help to identify patients who will respond well to immunotherapy. Modulation of TLS formation through the use of chemokines/cytokines, immunotherapy, or induction of high endothelial vein to interfere with tumor growth has been studied extensively in PHC and other cancers. In addition, new tools such as genetic interventions, cellular crosstalk, preoperative radiotherapy, and advances in materials science have been shown to influence the prognosis of malignant tumors by modulating TLS production. These can also be used to develop PHC treatment.

Citing Articles

[Clinical significance of tertiary lymphoid structure maturity in colorectal cancer patients].

Zheng J, Yu J, Xie J, Chen D, Deng H Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024; 53(6):765-771.

PMID: 39628410 PMC: 11736343. DOI: 10.3724/zdxbyxb-2024-0320.

Low CD8+ Density Variation and R1 Surgical Margin as Independent Predictors of Early Post-Resection Recurrence in HCC Patients Meeting Milan Criteria.

Stulpinas R, Jakiunaite I, Sidabraite A, Rasmusson A, Zilenaite-Petrulaitiene D, Strupas K Curr Oncol. 2024; 31(9):5344-5353.

PMID: 39330022 PMC: 11431076. DOI: 10.3390/curroncol31090394.

Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances.

Wang X, Yuan Z, Li Z, He X, Zhang Y, Wang X Front Immunol. 2024; 15:1354313.

PMID: 38426090 PMC: 10902128. DOI: 10.3389/fimmu.2024.1354313.

Heterogeneity of tertiary lymphoid structures in cancer.

You X, Koop K, Weigert A Front Immunol. 2023; 14:1286850.

PMID: 38111571 PMC: 10725932. DOI: 10.3389/fimmu.2023.1286850.

Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy.

Zou X, Guan C, Gao J, Shi W, Cui Y, Zhong X Front Immunol. 2023; 14:1222719.

PMID: 37529035 PMC: 10388371. DOI: 10.3389/fimmu.2023.1222719.

References

Romana Delvecchio F, Goulart M, Fincham R, Bombadieri M, Kocher H . B cells in pancreatic cancer stroma. World J Gastroenterol. 2022; 28(11):1088-1101. PMC: 8985484. DOI: 10.3748/wjg.v28.i11.1088. View

Chen L, Taylor J, Sabins N, Lowe D, Qu Y, You Z . Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells. Cancer Gene Ther. 2013; 20(8):469-77. PMC: 3775601. DOI: 10.1038/cgt.2013.42. View

Huang K, Tan C, Reebye V, Chee C, Zacharoulis D, Habib R . MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models. Int J Mol Sci. 2021; 22(17). PMC: 8431011. DOI: 10.3390/ijms22179168. View

Sautes-Fridman C, Fridman W . TLS in Tumors: What Lies Within. Trends Immunol. 2015; 37(1):1-2. DOI: 10.1016/j.it.2015.12.001. View

Germain C, Gnjatic S, Dieu-Nosjean M . Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity. Front Immunol. 2015; 6:67. PMC: 4337382. DOI: 10.3389/fimmu.2015.00067. View

Zhu Q, Li N, Li F, Sang J, Deng H, Han Q . Association of LTBR polymorphisms with chronic hepatitis B virus infection and hepatitis B virus-related hepatocellular carcinoma. Int Immunopharmacol. 2017; 49:126-131. DOI: 10.1016/j.intimp.2017.05.031. View

Moussion C, Girard J . Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature. 2011; 479(7374):542-6. DOI: 10.1038/nature10540. View

Hill D, Ward A, Nicholson L, Jones G . Emerging roles for IL-6 family cytokines as positive and negative regulators of ectopic lymphoid structures. Cytokine. 2021; 146:155650. DOI: 10.1016/j.cyto.2021.155650. View

Luo R, Cheng Y, Chang D, Liu T, Liu L, Pei G . Tertiary lymphoid organs are associated with the progression of kidney damage and regulated by interleukin-17A. Theranostics. 2021; 11(1):117-131. PMC: 7681089. DOI: 10.7150/thno.48624. View

10.

Cheng W, Li H, Xi S, Zhang X, Zhu Y, Xing L . Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma. Nat Commun. 2021; 12(1):7142. PMC: 8654996. DOI: 10.1038/s41467-021-27525-9. View

11.

Schrama D, Thor Straten P, Fischer W, McLellan A, Brocker E, Reisfeld R . Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity. 2001; 14(2):111-21. DOI: 10.1016/s1074-7613(01)00094-2. View

12.

Tokunaga R, Nakagawa S, Sakamoto Y, Nakamura K, Naseem M, Izumi D . 12-Chemokine signature, a predictor of tumor recurrence in colorectal cancer. Int J Cancer. 2020; 147(2):532-541. PMC: 9371443. DOI: 10.1002/ijc.32982. View

13.

Hong S, Hwang H, Kim M, Lee T, Yim K, Won H . High Endothelial Venule with Concomitant High CD8+ Tumor-Infiltrating Lymphocytes Is Associated with a Favorable Prognosis in Resected Gastric Cancer. J Clin Med. 2020; 9(8). PMC: 7464373. DOI: 10.3390/jcm9082628. View

14.

Lu C, Rong D, Hui B, He X, Jiang W, Xu Y . CircETFA upregulates CCL5 by sponging miR-612 and recruiting EIF4A3 to promote hepatocellular carcinoma. Cell Death Discov. 2021; 7(1):321. PMC: 8556257. DOI: 10.1038/s41420-021-00710-x. View

15.

Lin Q, Tao P, Wang J, Ma L, Jiang Q, Li J . Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors. Oncoimmunology. 2020; 9(1):1747339. PMC: 7153826. DOI: 10.1080/2162402X.2020.1747339. View

16.

Sautes-Fridman C, Petitprez F, Calderaro J, Fridman W . Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019; 19(6):307-325. DOI: 10.1038/s41568-019-0144-6. View

17.

Jamaly S, Rakaee M, Abdi R, Tsokos G, Fenton K . Interplay of immune and kidney resident cells in the formation of tertiary lymphoid structures in lupus nephritis. Autoimmun Rev. 2021; 20(12):102980. DOI: 10.1016/j.autrev.2021.102980. View

18.

Berteloot L, Molina T, Bruneau J, Picard C, Barlogis V, Secq V . Alternative pathways for the development of lymphoid structures in humans. Proc Natl Acad Sci U S A. 2021; 118(29). PMC: 8307690. DOI: 10.1073/pnas.2108082118. View

19.

Zhang M, Pang H, Zhao W, Li Y, Yan L, Dong Z . VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma. BMC Cancer. 2018; 18(1):511. PMC: 5932869. DOI: 10.1186/s12885-018-4435-1. View

20.

Brown J, Dorfman D, Ma F, Sullivan E, Munoz O, Wood C . Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003; 170(3):1257-66. DOI: 10.4049/jimmunol.170.3.1257. View