Epigenetic modifications of the immune-checkpoint genes CTLA4 and PDCD1 in non-small cell lung cancer results in increased expression

Marwitz, Sebastian; Scheufele, Swetlana; Perner, Sven; Reck, Martin; Ammerpohl, Ole; Goldmann, Torsten

doi:10.1186/s13148-017-0354-2

Cited by 55 publications

(51 citation statements)

References 6 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consequently, DNA methylation might also be suitable as a quantitative surrogate biomarker for T cell exhaustion. Since CTLA-4 expression has been shown to correlate inversely with promoter methylation in various malignancies (33)(34)(35), CTLA4 hypomethylation in tumors might be a surrogate biomarker for the state of T cell exhaustion. Such a second mechanism might add to the ability of mCTLA4 to assess the amount of CTLA-4-expressing and ICB-responding tumor cells, thereby explaining its high performance as a predictive biomarker.…”

Section: Discussionmentioning

confidence: 99%

CTLA4 methylation predicts response to anti–PD-1 and anti–CTLA-4 immunotherapy in melanoma patients

Goltz¹,

Gevensleben²,

Vogt³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

Recent years have witnessed the groundbreaking success of immune checkpoint blockage (ICB) in metastasized malignant melanoma. However, biomarkers predicting the response to ICB are still urgently needed. In the present study, we investigated CTLA4 promoter methylation (mCTLA4) in 470 malignant melanoma patients from The Cancer Genome Atlas (non-ICB cohort) and in 50 individuals with metastasized malignant melanomas under PD-1/CTLA-4-targeted immunotherapy (ICB cohort). mCTLA4 levels were quantified using the Infinium HumanMethylation450 BeadChip (non-ICB cohort) and methylation-specific quantitative real-time PCR in DNA formalin-fixed and paraffin-embedded tissues (ICB cohort). Methylation levels were associated with molecular and clinicopathological variables and analyzed with respect to response (irRECIST) and overall survival. CTLA-4 mRNA and mCTLA4 showed a significant inverse correlation (non-ICB cohort: Spearman's ρ = -0.416, P < 0.001). In ICB-treated melanoma patients, low mCTLA4 was further strongly correlated with response to therapy (P = 0.009, ANOVA) and overall survival (hazard ratio = 2.06 [95% CI: 1.29-3.29], P = 0.003). Our data strongly support the assumption that mCTLA4 predicts response to both anti-PD-1 and anti-CTLA-4 targeted ICB in melanoma and provides paramount information for the selection of patients likely to respond to ICB.

show abstract

Section: Discussionmentioning

confidence: 99%

CTLA4 methylation predicts response to anti–PD-1 and anti–CTLA-4 immunotherapy in melanoma patients

Goltz¹,

Gevensleben²,

Vogt³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

show abstract

“…Indeed, DNA methylation seems to control PD-1, PD-L1, PD-L2, and CTLA-4 gene expression; when these genes are silenced, the antigen presentation and the immune cytotoxic effects are inhibited [180,181]. The hypermethylation-derived silencing of CTLA-4 and PD-1 was also observed in baseline tumor biopsies compared to their pair-matched tissues in NSCLC patients [87]. In addition, in colorectal cancer, PD-L1 expression is associated with CpG island hypermethylation in a subpopulation of BRAF V600E carriers with high infiltration of CD3 + T cells [182].…”

Section: Emerging Evidence Supporting the Roles Of Dna Methylation Anmentioning

confidence: 96%

Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

Xiao

Nobre

Piñeiro

et al. 2020

JCM

View full text Add to dashboard Cite

Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.

show abstract

“…Immune checkpoint inhibitors are one of the promising treatments for cancer, especially the drugs targeting either the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed death 1 (PD1), yet the mechanisms are still not clear [36][37][38]. Here we examined the effect of miR-493 on PD-L1 and found that miR-493 regulates the expression of PD-L1 by c-JUN and then the sensitivity of EC cells to DDP.…”

Section: Mir-493 Regulates the Expression Of Pd-l1mentioning

confidence: 96%

miR-493 by regulating of c-Jun targets Wnt5a/PD-L1-inducing esophageal cancer cell development

Bian

Zhu

et al. 2019

Preprint

View full text Add to dashboard Cite

Background miRNA dysregulation has been implicated in cancer development.Methods In the present study, we use cell culture and transfection, the tissue specimens, RNA isolation and RT-PCR, Western blot and so on to explore the role of miR-493 in esophageal cancer.Results Overexpression of miR-493 attenuates esophageal cancer cell proliferation, migration, and invasion in vivo and in vitro. Moreover, miR-493 downregulation is an unfavorable factor in EC and negatively correlated with Wnt5A. The existence of miR-493 is also an important attribute of metabolism. Based on mechanism analyses, we show that miR-493 inhibits the activity of c-JUN and p-PI3K/p-AKT with enhanced p21 and directly regulates Wnt5A expression and function, while, c-JUN binds the promoter region of miR-493 and suppressed the expression of miR-493, forming a negative feedback loop. Moreover, miR-493 regulates the expression of PD-L1 by c-JUN and then the sensitivity of EC cells to DDP.Conclusions the results elucidate a molecular feedback loop that involves miR-493, Wnt5A, c-JUN and PD-L1 in EC. In future, these mechanistic findings provide a useful therapeutic option for the treatment of EC.

show abstract

Epigenetic modifications of the immune-checkpoint genes CTLA4 and PDCD1 in non-small cell lung cancer results in increased expression

Cited by 55 publications

References 6 publications

CTLA4 methylation predicts response to anti–PD-1 and anti–CTLA-4 immunotherapy in melanoma patients

CTLA4 methylation predicts response to anti–PD-1 and anti–CTLA-4 immunotherapy in melanoma patients

Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

miR-493 by regulating of c-Jun targets Wnt5a/PD-L1-inducing esophageal cancer cell development

Contact Info

Product

Resources

About