Mesenchymal Ovarian Cancer Cells Promote CD8 T Cell Exhaustion Through the LGALS3-LAG3 Axis

Overview

Journal NPJ Syst Biol Appl

Specialty Biology

Date 2023 Dec 12

PMID 38086828

Authors

Edward Yakubovich

David P Cook

Galaxia M Rodriguez

Barbara C Vanderhyden

Affiliations

Soon will be listed here.

Abstract

Cancer cells often metastasize by undergoing an epithelial-mesenchymal transition (EMT). Although abundance of CD8 T-cells in the tumor microenvironment correlates with improved survival, mesenchymal cancer cells acquire greater resistance to antitumor immunity in some cancers. We hypothesized the EMT modulates the immune response to ovarian cancer. Here we show that cancer cells from infiltrated/inflamed tumors possess more mesenchymal cells, than excluded and desert tumors. We also noted high expression of LGALS3 is associated with EMT in vivo, a finding validated with in vitro EMT models. Dissecting the cellular communications among populations in the tumor revealed that mesenchymal cancer cells in infiltrated tumors communicate through LGALS3 to LAG3 receptor expressed by CD8 T cells. We found CD8 T cells express high levels of LAG3, a marker of T cell exhaustion. The results indicate that EMT in ovarian cancer cells promotes interactions between cancer cells and T cells through the LGALS3 - LAG3 axis, which could increase T cell exhaustion in infiltrated tumors, dampening antitumor immunity.

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References

Cook D, Vanderhyden B . Transcriptional census of epithelial-mesenchymal plasticity in cancer. Sci Adv. 2022; 8(1):eabi7640. PMC: 8730603. DOI: 10.1126/sciadv.abi7640. View

van der Woude L, Gorris M, Halilovic A, Figdor C, de Vries I . Migrating into the Tumor: a Roadmap for T Cells. Trends Cancer. 2017; 3(11):797-808. DOI: 10.1016/j.trecan.2017.09.006. View

Ruffo E, Wu R, Bruno T, Workman C, Vignali D . Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor. Semin Immunol. 2019; 42:101305. PMC: 6920665. DOI: 10.1016/j.smim.2019.101305. View

Zhao L, Wang H, Xu K, Liu X, He Y . Update on lymphocyte-activation gene 3 (LAG-3) in cancers: from biological properties to clinical applications. Chin Med J (Engl). 2022; 135(10):1203-1212. PMC: 9337260. DOI: 10.1097/CM9.0000000000001981. View

Nhokaew W, Kleebkaow P, Chaisuriya N, Kietpeerakool C . Programmed Death Ligand 1 (PD-L1) Expression in Epithelial Ovarian Cancer: A Comparison of Type I and Type II Tumors. Asian Pac J Cancer Prev. 2019; 20(4):1161-1169. PMC: 6948887. DOI: 10.31557/APJCP.2019.20.4.1161. View

Demotte N, Wieers G, Van Der Smissen P, Moser M, Schmidt C, Thielemans K . A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res. 2010; 70(19):7476-88. DOI: 10.1158/0008-5472.CAN-10-0761. View

Chihara N, Madi A, Kondo T, Zhang H, Acharya N, Singer M . Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature. 2018; 558(7710):454-459. PMC: 6130914. DOI: 10.1038/s41586-018-0206-z. View

Shayesteh L, Lu Y, Kuo W, Baldocchi R, Godfrey T, Collins C . PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999; 21(1):99-102. DOI: 10.1038/5042. View

Hapke R, Haake S . Hypoxia-induced epithelial to mesenchymal transition in cancer. Cancer Lett. 2020; 487:10-20. PMC: 7336507. DOI: 10.1016/j.canlet.2020.05.012. View

10.

Whitehair R, Peres L, Mills A . Expression of the Immune Checkpoints LAG-3 and PD-L1 in High-grade Serous Ovarian Carcinoma: Relationship to Tumor-associated Lymphocytes and Germline BRCA Status. Int J Gynecol Pathol. 2019; 39(6):558-566. DOI: 10.1097/PGP.0000000000000657. View

11.

Chen H, Fermin A, Vardhana S, Weng I, Lo K, Chang E . Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proc Natl Acad Sci U S A. 2009; 106(34):14496-501. PMC: 2732795. DOI: 10.1073/pnas.0903497106. View

12.

Nugteren S, Samsom J . Secretory Leukocyte Protease Inhibitor (SLPI) in mucosal tissues: Protects against inflammation, but promotes cancer. Cytokine Growth Factor Rev. 2021; 59:22-35. DOI: 10.1016/j.cytogfr.2021.01.005. View

13.

Kim H, Lin Y, Geddes T, Yang J, Yang P . CiteFuse enables multi-modal analysis of CITE-seq data. Bioinformatics. 2020; 36(14):4137-4143. DOI: 10.1093/bioinformatics/btaa282. View

14.

Imai Y, Hasegawa K, Matsushita H, Fujieda N, Sato S, Miyagi E . Expression of multiple immune checkpoint molecules on T cells in malignant ascites from epithelial ovarian carcinoma. Oncol Lett. 2018; 15(5):6457-6468. PMC: 5876465. DOI: 10.3892/ol.2018.8101. View

15.

Sabbatino F, Liguori L, Polcaro G, Salvato I, Caramori G, Salzano F . Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients. Int J Mol Sci. 2020; 21(19). PMC: 7582904. DOI: 10.3390/ijms21197295. View

16.

Zhang L, Conejo-Garcia J, Katsaros D, Gimotty P, Massobrio M, Regnani G . Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177. View

17.

Fei Z, Deng Z, Zhou L, Li K, Xia X, Xie R . PD-L1 Induces Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma Cells Through Activation of the PI3K/AKT Pathway. Oncol Res. 2019; 27(7):801-807. PMC: 7848446. DOI: 10.3727/096504018X15446984186056. View

18.

Chen E, Tan C, Kou Y, Duan Q, Wang Z, Meirelles G . Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013; 14:128. PMC: 3637064. DOI: 10.1186/1471-2105-14-128. View

19.

Andrews L, Marciscano A, Drake C, Vignali D . LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017; 276(1):80-96. PMC: 5338468. DOI: 10.1111/imr.12519. View

20.

Zhang Y, Weinberg R . Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018; 12(4):361-373. PMC: 6186394. DOI: 10.1007/s11684-018-0656-6. View