LAG3 and its emerging role in cancer immunotherapy

Abstract

Immunotherapy has become a major form of cancer therapy after chemotherapy, radiotherapy, and targeted therapy. Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD1), anti-programmed cell death ligand 1 (PDL1), and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4), are widely studied in cancer immunotherapy.1, 2 However, a considerable percentage of tumor patients fail to respond to ICI monotherapy.3 Researchers have focused on enhancing mono-ICI efficacy through combination therapy or exploring novel immunotherapy targets. Lymphocyte-associated gene 3 (LAG3), a promising immune checkpoint, has received increasing attention recently. In this study, we described the biology of LAG3 and its function in cancer immunology, explored the multiomics characteristics of LAG3 utilizing a bioinformatics database, and provided perspective on the applications of single therapy or potential combination strategies for LAG3-targeting agents. LAG3 is a type I transmembrane protein that can be cut by metalloproteinase to release soluble LAG3 (sLAG3). LAG3 is expressed on CD4+, CD8+, regulatory T (Treg) cell, natural killer cell, B cell, and other immune cells.4 LAG3 has been reported to play a negative regulatory role in cancer immunology by interacting with its ligands, including major histocompatibility complex class II (MHC II), galectin-3, liver sinusoidal endothelial cell lectin, and fibrinogen-like protein 15, 6 (Figure 1A). For example, the LAG3–MHC II interaction can downregulate T cell proliferation and protect melanoma cells from drug-induced apoptosis.7, 8 sLAG3 expression was positively correlated with dendritic cell migration and T cell antitumor ability.9 To better guide the application of LAG3-targeting agents in cancer immunotherapy, we explored the immunomodulatory role of LAG3 in the tumor microenvironment (TME). We utilized the Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia2.cancer-pku.cn) database to analyze the expression of LAG3 and other common immune checkpoints across 33 cancers (Figure 2A). The expression of lag3 in kidney renal clear cell carcinoma (KIRC), pancreatic adenocarcinoma (PAAD), skin cutaneous melanoma (SKCM), testicular germ cell tumors (TGCT), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), and head and neck squamous cell carcinoma (HNSC) was significantly higher than in paired normal tissues, suggesting that blocking LAG3 may have a remarkable antitumor effect in these cancers. The expressions of lag3 and pdcd1 in TGCT, lag3 and ctla4 in HNSC and PAAD, lag3, pdcd1, and ctla4 in SKCM, and lag3, pdcd1, cd274, and ctla4 in DLBC were significantly higher than in paired normal tissues. This provides a theoretical basis for LAG3-targeting agents in combination with other common ICIs. We utilized the Tumor and Immune System Interaction Database (TISIDB) (http://cis.Hku.hk/TISIDB) to show the correlation between lag3 expression and tumor infiltrating lymphocyte (TIL) abundance, immunoregulatory factors, and chemokines across 30 cancer types (Figure 2B). The results showed that (1) lag3 expression was correlated with the abundance of multiple TILs, such as activated CD8+ T cell, Treg cell, and myeloid-derived suppressor cell, which supports the dual negative regulatory role of LAG3 in TME. LAG3 downregulates the antitumor efficacy of effector cell and enhances the inhibitory effect of suppressor cell.10 (2) Lag3 expression was positively associated with other immune checkpoints, such as pdcd1 and ctla4 in multiple cancers. Similar conclusions can be drawn from the GEPIA database (Figure 3). Lag3 expression was highly correlated with pdcd1 in SKCM and kidney renal papillary cell carcinoma (KIRP), suggesting that LAG3 and PD1 cotargeted immunotherapy may induce strong synergistic antitumor properties in both cancers. (3) Lag3 expression was positively correlated with many immunostimulators, such as cd80 and cd86, suggesting that LAG3 regulates immune homeostasis together with immunostimulators. (4) Lag3 expression was positively correlated with almost all MHC-related genes, suggesting that LAG3 may interact with MHC molecules, other than MHC II. (5) Lag3 expression was positively correlated with reported chemokines and chemokine receptors, such as cxcl2, cxcl5, and ccr2. Therefore, the relationship between lag3 and chemokines needs to be further investigated. Further correlations between lag3, pdcd1, cd274, and ctla4 expression and the clinical prognosis across 30 cancer types were analyzed utilizing TISIDB (Figure 2C). The high expression of lag3 was negatively correlated with the overall survival (OS) of KIRC, KIRP, brain lower grade glioma (LGG), and uveal melanoma (UVM) patients, suggesting that lag3 plays a pivotal role in promoting tumor growth in these tumors. The following high expressions were all negatively correlated: pdcd1 and the OS of KIRC patients, cd274 and the OS of LGG and PAAD patients, ctla4 and the OS of adrenocortical carcinoma, KIRC, KIRP, and UVM patients. We obtained similar results from the GEPIA database (Figure 2D). Interestingly, lag3 expression was positively correlated with the OS of patients with several types of tumors (Figure 2C), which is contradictory to the inhibitory role of LAG3 in the immune system. It may be due to the complicated tumor environment and different clinical features, such as the disease stage, initial treatments, and other heterogeneous factors in databases, that deserve further exploration. There are two types of LAG3-targeting agents used as antitumor immunotherapies: LAG3 soluble dimeric recombinant protein named IMP321 and LAG3 mAb (Figure 1B). IMP321 acts as an antigen-presenting cell activator to exert an antitumor effect. LAG3 mAb blocks the binding of LAG3 and its ligands to improve the antitumor activity of the host, which is widely applied in drug discovery. Dozens of IMP321 and LAG3 mAb-related clinical trials for various cancers are currently underway, most of which are combined with anti-PD1 (Table 1). LAG3 and PD1 / PDL1 / CTLA4 bispecific antibody immunotherapy is also in progress (Table S1). BMS986016 Relatlimab ICIs have greatly benefited tumor patients, and combination therapy improved the efficacy of ICIs. LAG3 is a promising checkpoint that negatively regulates T cell activation and indicates a poor prognosis for KIRC, KIRP, and many other tumors. The single application of LAG3-targeting agents in the dominant population and in combination with other ICIs, such as anti-PD1 / PDL1 / CTLA4, is expected to benefit more tumor patients. We hope that more clinical trials of LAG3-targeting agents in combination with chemotherapy, radiotherapy, and targeted therapy could be performed to obtain encouraging results. The authors would like to sincerely thank the open-access databases for data sharing and processing. The authors declare that they have no competing interests. Q.L. contributed to the design of the review and revised the article, had full access to all the contents included in this study, and took responsibility for the integrity of the data and the accuracy of the data analysis. M.W. and J.J. collected the literature. M.W. performed the bioinformatics analysis, prepared the figures, and performed the data interpretation. M.W., Q.D., Y.W., and Y.L. wrote the main manuscript text. All the authors contributed to the review and revision of the manuscript, and all authors read and approved the final manuscript. All data generated or analyzed during this study are included. All authors approved the final manuscript for publication. This work was supported by the Research Foundation of Beijing Friendship Hospital, Capital Medical University (No. yyqdky2019-40 and No. yyzscq202003). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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