LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

Klümper, Niklas; Ralser, Damian J.; Bawden, Emma Grace; Landsberg, Jenny; Zarbl, Romina; Kristiansen, Glen; Toma, Marieta; Ritter, Manuel; Hölzel, Michael; Ellinger, Jörg; Dietrich, Dimo

doi:10.1136/jitc-2020-000552

Cited by 84 publications

(76 citation statements)

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“…Interestingly, the inverse correlation between LAG3 and T-bet is bidirectionally causal (i.e., deletion of either T-bet or LAG3 increases the expression of the other) on murine T cells, suggesting that LAG3 promotes exhaustion and vice-versa ( 7 , 22 , 23 ). Methylation, particularly of the LAG3 promoter, appears to tightly regulate LAG3 expression ( 24 , 25 ).…”

Section: Expressionmentioning

confidence: 99%

LAG3’s Enigmatic Mechanism of Action

2021

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LAG3 is an important immune checkpoint with relevance in cancer, infectious disease and autoimmunity. However, despite LAG3’s role in immune exhaustion and the great potential of LAG3 inhibition as treatment, much remains unknown about its biology, particularly its mechanism of action. This review describes the knowns, unknowns and controversies surrounding LAG3. This includes examination of how LAG3 is regulated transcriptionally and post-translationally by endocytosis and proteolytic cleavage. We also discuss the interactions of LAG3 with its ligands and the purpose thereof. Finally, we review LAG3’s mechanism of action, including the roles of LAG3 intracellular motifs and the lack of a role for CD4 competition. Overall, understanding the biology of LAG3 can provide greater insight on LAG3 function, which may broaden the appreciation for LAG3’s role in disease and potentially aid in the development of targeted therapies.

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Section: Expressionmentioning

confidence: 99%

LAG3’s Enigmatic Mechanism of Action

2021

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“…Furthermore, the role of LAG3 methylation in melanoma cells needs further evaluation. Recently, LAG3 expression in clear cell renal carcinoma cell lines and a tumor cell-intrinsic LAG3 protein expression was reported [9] . However, knowledge of tumor cell-intrinsic expression of the LAG3 protein in melanoma is scarce.…”

Section: Discussionmentioning

confidence: 99%

“…in melanoma and colorectal carcinoma [8] . In addition, a recent report suggests a LAG3 expression by tumor cells as shown in clear cell renal cell carcinomas [9] .…”

Section: Introductionmentioning

confidence: 94%

“…On the opposite, high expression of MHC class II as a ligand for LAG3 on tumor cells seems to portend a poorer prognosis and may indicate exhaustion of tumor infiltrating T cells in melanoma [29] . A correlative analysis in clear cell renal cell carcinoma demonstrated prognostic significance for LAG3 methylation and mRNA expression, with high LAG3 expression indicating adverse overall survival [9] . This result was confirmed in other studies on metastatic renal cell cancer [24] .…”

Section: Introductionmentioning

confidence: 99%

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Molecular, clinicopathological, and immune correlates of LAG3 promoter DNA methylation in melanoma

et al. 2020

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Background The co-receptor lymphocyte-activation gene-3 (LAG3, LAG-3, CD223) is a potential target for immune checkpoint inhibition immunotherapies. However, little is known about the biological and clinical significance of LAG3 DNA methylation in melanoma and its microenvironment. Methods We evaluated LAG3 promoter and gene body methylation in a cohort of N = 470 melanoma patients obtained from The Cancer Genome Atlas (TCGA cohort), an independent cohort of N = 120 patients from the University Hospital Bonn, and in subsets of peripheral blood leukocytes, melanocytes, and melanoma cell lines. We validated the association of LAG3 methylation with mRNA expression in vitro in the melanoma cell line A375 treated with the hypomethylating agent 5-azacytidine and stimulated with interferon-γ. Finally, we investigated correlations between LAG3 methylation and progression-free survival in patients treated with immune checkpoint blockade (ICB cohort, N = 118). Findings Depending on the analysed locus (promoter, gene body) we found region-dependent significant LAG3 methylation differences between monocytes, B cells, CD8 + and CD4 + T cells, regulatory T cells, melanocytes, and melanoma cell lines. In tumor tissues, methylation correlated significantly with LAG3 mRNA expression, immune cell infiltrates (histopathologic lymphocyte score and RNA-Seq signatures of distinct immune infiltrates), and an interferon-γ signature. Finally, LAG3 methylation was associated with overall survival in the TCGA cohort and progression-free survival in the ICB cohort. We detected basal LAG3 mRNA expression in the melanoma cell A375 and an interferon-γ inducible expression after demethylation with 5-azacytidine. Interpretation Our study points towards an epigenetic regulation of LAG3 via promoter methylation and suggests a prognostic and predictive significance of LAG3 methylation in melanoma. Our results give insight in the tumor cell-intrinsic transcriptional regulation of LAG3 in melanoma. In perspective, our results might pave the way for investigating LAG3 methylation as a predictive biomarker for response to anti-LAG3 immune checkpoint blockage. Funding A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

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“…Of particular note is the 24 connected group of T cell regulatory genes PDL1, CD80, LAG3, HAVRC2, and IL10. LAG3 has 25 been shown to be of importance in immune infiltration and overall survival in renal cell 26 carcinoma (Klümper et al, 2020), acts as an important player in intratumoral T cell exhaustion in 1 lymphoma (Yang et al, 2017), and has been suggested as a potential therapeutic target for new 2 ICB strategies (Long et al, 2018). HAVRC2 (also known as TIM3) has been shown to be an 3 important inhibitory T cell receptor, as well as a defining characteristic of exhausted T cells in 4 concert with PD1 (Lee et al, 2016), (Wolf et al, 2020).…”

Section: Pdl1 5mentioning

confidence: 99%

Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

Erbe

Wang

Zaidi

et al. 2020

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1Advanced age is strongly correlated with both increased cancer incidence and general immune 2 decline. The immune tumor microenvironment (ITME) has been established as an important 3 prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune 4 decline is an important consideration for the treatment of a large subset of cancer patients. 5Current studies of aging-related immune alterations are predominantly performed on non-6 cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration. 7We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the 8 Genotype-Tissue Expression project to distinguish normal age-related immune alterations from 9 age-related changes in tumor immune infiltration. We demonstrate that while there is overlap 10 between the normal immune aging phenotype and that of the ITME, there are several changes 11 in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and 12Macrophage populations. These results suggest that aged immune cells are more susceptible to 13 tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which 14 creates an unfavorable ITME in older patients in excess of normal immune decline with age and 15 may inform the application of existing and emerging immunotherapies for this large population 16 of patients. We additionally identify that age-related increases in tumor mutational burden are 17 associated with decreased DNA methylation and increased expression of the immune 18 checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic 19 application of immune checkpoint blockade in older patients. 20 21

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LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

Cited by 84 publications

References 48 publications

LAG3’s Enigmatic Mechanism of Action

LAG3’s Enigmatic Mechanism of Action

Molecular, clinicopathological, and immune correlates of LAG3 promoter DNA methylation in melanoma

Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

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