Restoration of MHC-I on Tumor Cells by Fhit Transfection Promotes Immune Rejection and Acts as an Individualized Immunotherapeutic Vaccine

Pulido, María; Chamorro, Virginia; Romero, Irene Gallego; Algarra, Ignacio; S-Montalvo, Alba; Collado, Antonia; Garrido, Federico; García-Lora, Angel

doi:10.3390/cancers12061563

Cited by 14 publications

(8 citation statements)

References 53 publications

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“…We also observed that late Panobinostat but not early Panobinostat led to a significant loss in DNA methylation at a loci in the gene Fragile Histidine Triad Diadenosine Triphosphtatase (FHIT). Recent work has shown that FHIT gene transfection in mice restores MHC-I expression, and Panobinostat has been shown to augment the expression of MHC genes and HIV antigen processing and presentation [57][58][59][60].…”

Section: Discussionmentioning

confidence: 99%

Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound

Corley

Pang

Rasmussen

et al. 2021

Aids

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Objective: This study aimed to identify candidate host epigenetic biomarkers predicting latency reversal agents (LRA) efficacy and HIV-1 rebound kinetics during analytical treatment interruption (ATI).Design: Retrospective longitudinal epigenetic profiling study from 13 people with HIV (PWH) on virologically suppressive antiretroviral therapy (ART) that participated in a LRA (HDAC inhibitor) clinical trial (NCT01680094) and a subsequent optional ATI to monitor for viral recrudescence after ART cessation.Methods: Genome-wide DNA methylation (DNAm) in purified CD4 þ T cells was measured at single-nucleotide resolution using the Infinium MethylationEPIC array. HIV-1 DNA and RNA measures were previously assessed by PCR-based methods and the association of DNAm levels at regulatory sites of the human genome were examined with reservoir size, responsiveness to LRA, and time to viral rebound following ATI.Results: A distinct set of 15 candidate DNAm sites in purified CD4 þ T cells at baseline pre-LRA and pre-ATI significantly correlated with time to viral rebound. Eight of these DNAm sites occurred in genes linked to HIV-1 replication dynamics including (SEP-SECS, cg19113954), (MALT1, cg15968021), (CPT1C, cg14318858), (CRTAM, cg10977115), (B4GALNT4, cg04663285), (IL10, cg16284789), (TFPI2, cg19645693), and (LIFR, cg26437306); with the remaining sites at intergenic regions containing regulatory elements. Moreover, baseline DNAm states related to total HIV-1 DNA levels and the fold change in unspliced cell-associated HIV RNA following LRA treatment. Conclusion:Preexisting host epigenetic states may determine HIV-1 rebound kinetics and reservoir maintenance. These findings suggest integrating a suite of DNA methylation markers to improve optimal participant selection and drug regimen in future HIV cure clinical trials.

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Section: Discussionmentioning

confidence: 99%

Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound

Corley

Pang

Rasmussen

et al. 2021

Aids

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“…Additionally, loss of Fhit expression in human breast tumors is associated with loss of HLA-I molecules. 68 The non-classical HLA-I molecules (notably HLA-E and HLA-G) have slightly different regulatory sequences, providing the opportunity for differential expression of classical and non-classical HLA genes through transcription factor variation (figure 2B). Both regulatory modules mentioned above can be identified in the HLA-E and HLA-F promoter regions, however in HLA-E the κB1 and κB2 and ISRE sites are different from the classical genes meaning that HLA-E is thought to be not induced by NF-κB, although an upstream GAS site provides strong inducibility by IFN-γ.…”

Section: Transcriptional Silencingmentioning

confidence: 99%

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Hazini

Fisher

Seymour

2021

J Immunother Cancer

103

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It is now well accepted that many tumors undergo a process of clonal selection which means that tumor antigens arising at various stages of tumor progression are likely to be represented in just a subset of tumor cells. This process is thought to be driven by constant immunosurveillance which applies selective pressure by eliminating tumor cells expressing antigens that are recognized by T cells. It is becoming increasingly clear that the same selective pressure may also select for tumor cells that evade immune detection by acquiring deficiencies in their human leucocyte antigen (HLA) presentation pathways, allowing important tumor antigens to persist within cells undetected by the immune system. Deficiencies in antigen presentation pathway can arise by a variety of mechanisms, including genetic and epigenetic changes, and functional antigen presentation is a hard phenomenon to assess using our standard analytical techniques. Nevertheless, it is likely to have profound clinical significance and could well define whether an individual patient will respond to a particular type of therapy or not. In this review we consider the mechanisms by which HLA function may be lost in clinical disease, we assess the implications for current immunotherapy approaches using checkpoint inhibitors and examine the prognostic impact of HLA loss demonstrated in clinical trials so far. Finally, we propose strategies that might be explored for possible patient stratification.

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“…Re-expression of Fhit restored the MHC-I expression in this clone. The same group recently reported that in MHC-I negative breast cancers the loss of NLRC5 is less frequent than the loss of FHIT, and that FHIT could be used to restore MHC-I expression [ 254 ]. As FHIT does not upregulate NLRC5 expression, the molecular pathways by which FHIT upregulates MHC-I remains to be determined [ 254 ].…”

Section: Restoring Mhc-i Expression In Cancersmentioning

confidence: 99%

The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy

Shukla

Cloutier

Santharam

et al. 2021

IJMS

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The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells circumvent immune surveillance using diverse strategies. A key mechanism of cancer immune evasion is downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM). Even though impaired MHC-I expression in cancers is well-known, reversing the MHC-I defects remains the least advanced area of tumor immunology. The discoveries that NLRC5 is the key transcriptional activator of MHC-I and APM genes, and genetic lesions and epigenetic modifications of NLRC5 are the most common cause of MHC-I defects in cancers, have raised the hopes for restoring MHC-I expression. Here, we provide an overview of cancer immunity mediated by CD8+ T cells and the functions of NLRC5 in MHC-I antigen presentation pathways. We describe the impressive advances made in understanding the regulation of NLRC5 expression, the data supporting the antitumor functions of NLRC5 and a few reports that argue for a pro-tumorigenic role. Finally, we explore the possible avenues of exploiting NLRC5 for cancer immunotherapy.

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Restoration of MHC-I on Tumor Cells by Fhit Transfection Promotes Immune Rejection and Acts as an Individualized Immunotherapeutic Vaccine

Cited by 14 publications

References 53 publications

Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound

Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound

Deregulation of HLA-I in cancer and its central importance for immunotherapy

The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy

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