Comprehensive Transcriptomic Analysis Reveals the Role of the Immune Checkpoint HLA-G Molecule in Cancers

Xu, Huihui; Gan, Jing; Xu, Dan-Ping; Li, Lü; Yan, Wei‐Hua

doi:10.3389/fimmu.2021.614773

Cited by 11 publications

(5 citation statements)

References 100 publications

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“…HLA-G can interact with the inhibitory receptor Immunoglobulin-Like Transcript 2 (ILT2) in the blood and be secreted as a free soluble form (sHLA-G) or through extracellular vesicles [ 47 ]. Recently, new approaches revealed that the blockage of the HLA-G/ILT axis, could be insightful for the development of effective anti-tumor treatments strategies [ 59 , 60 , 61 ]. Since HLA-G exists in several polymorphs that affect both the protein expression levels and its peptide-binding cleft, targeting peptide binding cleft of the most common HLA-G polymorphs can also be suggested as a therapeutic strategy [ 31 ].…”

Section: Functions Of Hla-g In Diseasesmentioning

confidence: 99%

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases

et al. 2022

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Human Leukocyte Antigen-G (HLA-G), a polymorphic non-classical HLA (HLA-Ib) with immune-regulatory properties in cancers and infectious diseases, presents both membrane-bound and soluble (sHLA-G) isoforms. Polymorphism has implications in host responses to pathogen infections and in pathogenesis. Differential expression patterns of HLA-G/sHLA-G or its polymorphism seem to be related to different pathological conditions, potentially acting as a disease progression biomarker. Pathogen antigens might be involved in the regulation of both membrane-bound and sHLA-G levels and impact immune responses during co-infections. The upregulation of HLA-G in viral and bacterial infections induce tolerance to infection. Recently, sHLA-G was found useful to identify the prognosis of Coronavirus disease 2019 (COVID-19) among patients and it was observed that the high levels of sHLA-G are associated with worse prognosis. The use of pathogens, such as Plasmodium falciparum, as immune modulators for other infections could be extended for the modulation of membrane-bound HLA-G in COVID-19-infected tissues. Overall, such information might open new avenues concerning the effect of some pathogens such as parasites in decreasing the expression level of HLA-G to restrict pathogenesis in some infections or to influence the immune responses after vaccination among others.

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Section: Functions Of Hla-g In Diseasesmentioning

confidence: 99%

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases

et al. 2022

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“…Although these new immunotherapies represent a huge improvement in the field of cancer therapies, early or late resistance emerge in the majority of the patients [ 1 , 2 ]. There is thus a high medical need to better understand the mechanisms underlying the control of immune checkpoint gene expression that is so far essentially described at the transcription level [ 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

Biswas

Guemiri

Cadix

et al. 2022

Cancers

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Targeting the translation initiation complex eIF4F, which binds the 5′ cap of mRNAs, is a promising anti-cancer approach. Silvestrol, a small molecule inhibitor of eIF4A, the RNA helicase component of eIF4F, inhibits the translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor, which, in turn, reduces the transcription of the gene encoding one of the major immune checkpoint proteins, i.e., programmed death ligand-1 (PD-L1) in melanoma cells. A large proportion of human genes produce multiple mRNAs differing in their 3′-ends through the use of alternative polyadenylation (APA) sites, which, when located in alternative last exons, can generate protein isoforms, as in the STAT1 gene. Here, we provide evidence that the STAT1α, but not STAT1β protein isoform generated by APA, is required for silvestrol-dependent inhibition of PD-L1 expression in interferon-γ-treated melanoma cells. Using polysome profiling in activated T cells we find that, beyond STAT1, eIF4A inhibition downregulates the translation of some important immune-related mRNAs, such as the ones encoding TIM-3, LAG-3, IDO1, CD27 or CD137, but with little effect on the ones for BTLA and ADAR-1 and no effect on the ones encoding CTLA-4, PD-1 and CD40-L. We next apply RT-qPCR and 3′-seq (RNA-seq focused on mRNA 3′ ends) on polysomal RNAs to analyze in a high throughput manner the effect of eIF4A inhibition on the translation of APA isoforms. We identify about 150 genes, including TIM-3, LAG-3, AHNAK and SEMA4D, for which silvestrol differentially inhibits the translation of APA isoforms in T cells. It is therefore crucial to consider 3′-end mRNA heterogeneity in the understanding of the anti-tumor activities of eIF4A inhibitors.

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“…NF‐κB can promote tumour survival via modifying apoptosis, cause inflammatory microenvironment by interacting with interleukins, and affect NSCLC survival [ 34 ]. Meanwhile, HLA‐G , a member of the MHC class I, is a well‐established immune checkpoint that plays an important regulatory role in tumour immune response [ 35 , 36 ]. HLA‐G can inhibit the functions of NK and T cells, suppress the immune response, help tumour cells escape immune surveillance, and lead to poor prognosis of NSCLC patients [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

A trans‐omics assessment of gene–gene interaction in early‐stage NSCLC

Chen

Song

et al. 2022

Molecular Oncology

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Epigenome‐wide gene–gene (G × G) interactions associated with non‐small‐cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three‐step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with PBonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two‐phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans‐omics analysis, which had significant (P ≤ 0.05) epigenetic cis‐regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (βinteraction = 0.018, P = 1.87 × 10−12), which mapped to RELA × HLA‐G (βinteraction = 0.218, P = 8.82 × 10−11) and cg08872738 × cg27077312 (βinteraction = −0.010, P = 1.16 × 10−11), which mapped to TUBA1B × TOMM40 (βinteraction =−0.250, P = 3.83 × 10−10). A trans‐omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans‐omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.

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Comprehensive Transcriptomic Analysis Reveals the Role of the Immune Checkpoint HLA-G Molecule in Cancers

Cited by 11 publications

References 100 publications

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases

Immunomodulatory Potential of Non-Classical HLA-G in Infections including COVID-19 and Parasitic Diseases

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

A trans‐omics assessment of gene–gene interaction in early‐stage NSCLC

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