LAG3 Immune Inhibitors: a Novel Strategy for Melanoma Treatment

Overview

Journal Front Oncol

Specialty Oncology

Date 2025 Jan 2

PMID 39743998

Authors

Renzheng Wu

Mingtang Zeng

Yuchen Zhang

Jianping He

Affiliations

Soon will be listed here.

Abstract

Melanoma, a highly aggressive skin cancer, poses significant challenges in treatment, particularly for advanced or metastatic cases. While immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1, has transformed melanoma management, many patients experience limited responses or develop resistance, highlighting the need for new therapeutic strategies. Lymphocyte activation gene 3 (LAG-3) has emerged as a promising target in cancer immunotherapy. LAG-3 inhibitors have shown potential in restoring T cell functions and enhancing anti-tumor immunity, particularly when used in combination with existing ICIs. This review discusses the latest advancements in LAG-3 inhibition for advanced melanoma, emphasizing its role in overcoming resistance and improving patient outcomes.

References

Trocchia M, Ventrici A, Modestino L, Cristinziano L, Ferrara A, Palestra F . Innate Immune Cells in Melanoma: Implications for Immunotherapy. Int J Mol Sci. 2024; 25(15). PMC: 11313504. DOI: 10.3390/ijms25158523. View

Li Y, Liang Z, Tian Y, Cai W, Weng Z, Chen L . High-affinity PD-1 molecules deliver improved interaction with PD-L1 and PD-L2. Cancer Sci. 2018; 109(8):2435-2445. PMC: 6113430. DOI: 10.1111/cas.13666. View

Huang C, Workman C, Flies D, Pan X, Marson A, Zhou G . Role of LAG-3 in regulatory T cells. Immunity. 2004; 21(4):503-13. DOI: 10.1016/j.immuni.2004.08.010. View

Gestermann N, Saugy D, Martignier C, Tille L, Fuertes Marraco S, Zettl M . LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures. Oncoimmunology. 2020; 9(1):1736792. PMC: 7422827. DOI: 10.1080/2162402X.2020.1736792. View

Souri Z, Wierenga A, Kroes W, van der Velden P, Verdijk R, Eikmans M . and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma. Cancers (Basel). 2021; 13(17). PMC: 8430821. DOI: 10.3390/cancers13174445. View

Guy C, Mitrea D, Chou P, Temirov J, Vignali K, Liu X . LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nat Immunol. 2022; 23(5):757-767. PMC: 9106921. DOI: 10.1038/s41590-022-01176-4. View

Camisaschi C, De Filippo A, Beretta V, Vergani B, Villa A, Vergani E . Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. J Invest Dermatol. 2014; 134(7):1893-1902. DOI: 10.1038/jid.2014.29. View

Tawbi H, Schadendorf D, Lipson E, Ascierto P, Matamala L, Castillo Gutierrez E . Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022; 386(1):24-34. PMC: 9844513. DOI: 10.1056/NEJMoa2109970. View

Robert C . LAG-3 and PD-1 blockade raises the bar for melanoma. Nat Cancer. 2022; 2(12):1251-1253. DOI: 10.1038/s43018-021-00276-8. View

10.

Burova E, Hermann A, Dai J, Ullman E, Halasz G, Potocky T . Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human -Knockin Mice. Mol Cancer Ther. 2019; 18(11):2051-2062. DOI: 10.1158/1535-7163.MCT-18-1376. View

11.

Du X, Tang F, Liu M, Su J, Zhang Y, Wu W . A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res. 2018; 28(4):416-432. PMC: 5939050. DOI: 10.1038/s41422-018-0011-0. View

12.

Atkinson V, Khattak A, Haydon A, Eastgate M, Roy A, Prithviraj P . Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma. J Immunother Cancer. 2020; 8(2). PMC: 7682474. DOI: 10.1136/jitc-2020-001681. View

13.

Fernandez E, Tamura D, Khan S, Momen S, Fassihi H, Sarkany R . Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers. Front Oncol. 2023; 13:1282823. PMC: 10634243. DOI: 10.3389/fonc.2023.1282823. View

14.

Huo J, Wang Y, Fu W, Lu N, Liu Z . The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application. Front Immunol. 2022; 13:956090. PMC: 9361790. DOI: 10.3389/fimmu.2022.956090. View

15.

Yu X, Huang X, Chen X, Liu J, Wu C, Pu Q . Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy. MAbs. 2019; 11(6):1139-1148. PMC: 6748621. DOI: 10.1080/19420862.2019.1629239. View

16.

Ming Q, Antfolk D, Price D, Manturova A, Medina E, Singh S . Structural basis for mouse LAG3 interactions with the MHC class II molecule I-A. Nat Commun. 2024; 15(1):7513. PMC: 11362559. DOI: 10.1038/s41467-024-51930-5. View

17.

Jiang H, Ni H, Zhang P, Guo X, Wu M, Shen H . PD-L1/LAG-3 bispecific antibody enhances tumor-specific immunity. Oncoimmunology. 2021; 10(1):1943180. PMC: 8237984. DOI: 10.1080/2162402X.2021.1943180. View

18.

Zhang Y, Yang R, Xu C, Zhang Y, Deng M, Wu D . Analysis of the immune checkpoint lymphocyte activation gene-3 (LAG-3) in endometrial cancer: An emerging target for immunotherapy. Pathol Res Pract. 2022; 236:153990. DOI: 10.1016/j.prp.2022.153990. View

19.

Maruhashi T, Sugiura D, Okazaki I, Shimizu K, Maeda T, Ikubo J . Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity. Immunity. 2022; 55(5):912-924.e8. DOI: 10.1016/j.immuni.2022.03.013. View

20.

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