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Open Access 01-12-2023 | Checkpoint Inhibitors | Research

LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study

Authors: Ken Arimura, Kenzo Hiroshima, Yoji Nagashima, Tadao Nakazawa, Akira Ogihara, Mami Orimo, Yasuto Sato, Hideki Katsura, Masato Kanzaki, Mitsuko Kondo, Etsuko Tagaya

Published in: BMC Cancer | Issue 1/2023

Abstract

Background

Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM.

Methods

We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan–Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed.

Results

LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM.

Conclusions

LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM.

Trial registration

This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022–0048) at Tokyo Women’s Medical University.

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Yates DH, Corrin B, Stidolph PN, Browne K. Malignant mesothelioma in southeast England: clinicopathological experience of 272 cases. Thorax. 1997;52:507–12. https://doi.org/10.1136/thx.52.6.507.CrossRefPubMedCentralPubMed

Remon J, Lianes P, Martínez S, Velasco M, Querol R, Zanui M. Malignant mesothelioma: new insights into a rare disease. Cancer Treat Rev. 2013;39:584–91. https://doi.org/10.1016/j.ctrv.2012.12.005.CrossRefPubMed

Janes SM, Alrifai D, Fennell DA. Perspectives on the treatment of malignant pleural mesothelioma. N Engl J Med. 2021;385:1207–18. https://doi.org/10.1056/NEJMra1912719.CrossRefPubMed

Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005;366:397–408. https://doi.org/10.1016/S0140-6736(05)67025-0.CrossRefPubMed

Yap TA, Aerts JG, Popat S, Fennell DA. Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer. 2017;17:475–88. https://doi.org/10.1038/nrc.2017.42.CrossRefPubMed

Reid A, de Klerk NH, Magnani C, Ferrante D, Berry G, Musk AW, et al. Mesothelioma risk after 40 years since first exposure to asbestos: a pooled analysis. Thorax. 2014;69:843–50. https://doi.org/10.1136/thoraxjnl-2013-204161.CrossRefPubMed

Liu B, van Gerwen M, Bonassi S, Taioli E; International Association for the Study of Lung Cancer Mesothelioma Task Force. Epidemiology of environmental exposure and malignant mesothelioma. J Thorac Oncol. 2017;12:1031–45. https://doi.org/10.1016/j.jtho.2017.04.002.

Szlosarek PW, Steele JP, Nolan L, Gilligan D, Taylor P, Spicer J, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol. 2017;3:58–66. https://doi.org/10.1001/jamaoncol.2016.3049.CrossRefPubMed

Zauderer MG, Szlosarek PW, Le Moulec S, Popat S, Taylor P, Planchard D, et al. EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2022;23:758–67. https://doi.org/10.1016/S1470-2045(22)00277-7.CrossRefPubMed

10.

Fennell DA, King A, Mohammed S, Greystoke A, Anthony S, Poile C, et al. Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial. Lancet Oncol. 2022;23:374–81. https://doi.org/10.1016/S1470-2045(22)00062-6.CrossRefPubMed

11.

Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–44. https://doi.org/10.1200/JCO.2003.11.136.CrossRefPubMed

12.

Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2021;397:375–86. https://doi.org/10.1016/S0140-6736(20)32714-8.CrossRefPubMed

13.

Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386:24–34. https://doi.org/10.1056/NEJMoa2109970.CrossRefPubMedCentralPubMed

14.

Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405. https://doi.org/10.1084/jem.171.5.1393.CrossRefPubMed

15.

Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell. 2019;176:334-347.e12. https://doi.org/10.1016/j.cell.2018.11.010.CrossRefPubMed

16.

Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–13. https://doi.org/10.1016/j.immuni.2004.08.010.CrossRefPubMed

17.

Shi AP, Tang XY, Xiong YL, Zheng KF, Liu YJ, Shi XG, et al. Immune checkpoint LAG3 and its ligand FGL1 in cancer. Front Immunol. 2021;12:785091. https://doi.org/10.3389/fimmu.2021.785091.CrossRefPubMed

18.

Gray SG. Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma. BMC Pulm Med. 2021;21:148. https://doi.org/10.1186/s12890-021-01513-7.CrossRefPubMedCentralPubMed

19.

Salaroglio IC, Kopecka J, Napoli F, Pradotto M, Maletta F, Costardi L, et al. Potential diagnostic and prognostic role of microenvironment in malignant pleural mesothelioma. J Thorac Oncol. 2019;14:1458–71. https://doi.org/10.1016/j.jtho.2019.03.029.CrossRefPubMed

20.

Chocarro L, Blanco E, Arasanz H, Fernández-Rubio L, Bocanegra A, Echaide M, et al. Clinical landscape of LAG-3-targeted therapy. Immunooncol Technol. 2022;14:100079. https://doi.org/10.1016/j.iotech.2022.100079.CrossRefPubMedCentralPubMed

21.

Huo JL, Wang YT, Fu WJ, Lu N, Liu ZS. The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application. Front Immunol. 2022;13:956090. https://doi.org/10.3389/fimmu.2022.956090.CrossRefPubMedCentralPubMed

22.

Andrews LP, Cillo AR, Karapetyan L, Kirkwood JM, Workman CJ, Vignali DAA. Molecular pathways and mechanisms of LAG3 in cancer therapy. Clin Cancer Res. 2022;28:5030–9. https://doi.org/10.1158/1078-0432.CCR-21-2390.CrossRefPubMedCentralPubMed

23.

Blum A, Wang P. Zenklusen JC. SnapShot: TCGA-analyzed tumors. Cell. 2018;173:530. https://doi.org/10.1016/j.cell.2018.03.059.CrossRefPubMed

24.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77:e108–10. https://doi.org/10.1158/0008-5472.CAN-17-0307.CrossRefPubMedCentralPubMed

25.

Zhao J, Yang Z, Tu M, Meng W, Gao H, Li MD, et al. Correlation between prognostic biomarker SLC1A5 and immune infiltrates in various types of cancers including hepatocellular carcinoma. Front Oncol. 2021;11:608641. https://doi.org/10.3389/fonc.2021.608641.CrossRefPubMedCentralPubMed

26.

Spearman C. The proof and measurement of association between two things. Int J Epidemiol. 2010;39:1137–50. https://doi.org/10.1093/ije/dyq191.CrossRefPubMed

27.

Arimura K, Sekine Y, Hiroshima K, Shimizu S, Shibata N, Kondo M, et al. PD-L1, FGFR1, PIK3CA, PTEN, and p16 expression in pulmonary emphysema and chronic obstructive pulmonary disease with resected lung squamous cell carcinoma. BMC Pulm Med. 2019;19:169. https://doi.org/10.1186/s12890-019-0913-8.CrossRefPubMedCentralPubMed

28.

Marcq E, Siozopoulou V, De Waele J, van Audenaerde J, Zwaenepoel K, Santermans E, et al. Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma. Oncoimmunology. 2016;6:e1261241. https://doi.org/10.1080/2162402X.2016.1261241.CrossRefPubMedCentralPubMed

29.

Peng C, Huggins MA, Wanhainen KM, Knutson TP, Lu H, Georgiev H, et al. Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8+ tissue-resident memory T cells. Immunity. 2022;55:98-114.e5. https://doi.org/10.1016/j.immuni.2021.11.017.CrossRefPubMed

30.

Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124:359–67. https://doi.org/10.1038/s41416-020-01048-4.CrossRefPubMed

31.

Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 2015;75:2139–45. https://doi.org/10.1158/0008-5472.CAN-15-0255.CrossRefPubMedCentralPubMed

32.

Kim TK, Vandsemb EN, Herbst RS, Chen L. Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat Rev Drug Discov. 2022;21:529–40. https://doi.org/10.1038/s41573-022-00493-5.33.CrossRefPubMed

33.

Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917–27. https://doi.org/10.1158/0008-5472.CAN-11-1620.CrossRefPubMed

Title: LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study
Authors: Ken Arimura
Kenzo Hiroshima
Yoji Nagashima
Tadao Nakazawa
Akira Ogihara
Mami Orimo
Yasuto Sato
Hideki Katsura
Masato Kanzaki
Mitsuko Kondo
Etsuko Tagaya
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Checkpoint Inhibitors
Pleural Mesothelioma
Pleural Mesothelioma
Biomarkers
Published in: BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-023-11636-1

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