Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid

Mora‐García, María de Lourdes; Dueñas‐González, Alfonso; Hernández‐Montes, Jorge; Cruz-Hernández, Erick de la; Pérez-Cárdenas, Enrique; Weiss‐Steider, Benny; Santiago‐Osorio, Edelmiro; Ortı́z-Navarrete, Vianney; Rosales, Victor H.; Cantú, David; Lizano-Soberón, Marcela; Rojo-Aguilar, Martha Patricia; García, Alberto Monroy

doi:10.1186/1479-5876-4-55

Cited by 59 publications

(29 citation statements)

References 42 publications

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“…Taken together, the high absolute levels of mRNAs encoding MHC-I components expressed in HPV+ head & neck and cervical carcinomas provide good evidence that high-risk HPV E7 is unable to efficiently block the IFN-γ induction of transcription of these genes in actual human tumors. Although this contrasts with the results of the studies listed above, our work agrees with other studies showing that various cervical cancer cell lines upregulate MHC-I in response to IFN-γ [ 59 , 60 , 61 ], and the treatment of HPV+ pre-cancerous cervical lesions in patients increased expression of at least HLA-B in a majority of cases [ 62 ]. It should be noted that the levels of MHC-I heavy chain mRNAs are statistically lower in HPV+ vs HPV− samples in the HNSC cohort ( Figure 1 ), despite the increased levels of IFN-γ ( Figure 7 ).…”

Section: Discussionsupporting

confidence: 76%

Analysis of Class I Major Histocompatibility Complex Gene Transcription in Human Tumors Caused by Human Papillomavirus Infection

Gameiro

Zhang

Ghasemi

et al. 2017

Viruses

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Oncoproteins from high-risk human papillomaviruses (HPV) downregulate the transcription of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus in tissue culture model systems. This could allow infected or transformed cells to evade the adaptive immune response. Using data from over 800 human cervical and head & neck tumors from The Cancer Genome Atlas (TCGA), we determined the impact of HPV status on the mRNA expression of all six MHC-I heavy chain genes, and the β2 microglobulin light chain. Unexpectedly, these genes were all expressed at high levels in HPV positive (HPV+) cancers compared with normal control tissues. Indeed, many of these genes were expressed at significantly enhanced levels in HPV+ tumors. Similarly, the transcript levels of several other components of the MHC-I peptide-loading complex were also high in HPV+ cancers. The coordinated expression of high mRNA levels of the MHC-I antigen presentation apparatus could be a consequence of the higher intratumoral levels of interferon γ in HPV+ carcinomas, which correlate with signatures of increased infiltration by T- and NK-cells. These data, which were obtained from both cervical and oral tumors in large human cohorts, indicates that HPV oncoproteins do not efficiently suppress the transcription of the antigen presentation apparatus in human tumors.

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Section: Discussionsupporting

confidence: 76%

Analysis of Class I Major Histocompatibility Complex Gene Transcription in Human Tumors Caused by Human Papillomavirus Infection

Gameiro

Zhang

Ghasemi

et al. 2017

Viruses

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“…Discovery of this methylation-mediated mechanism could have meaningful clinical implications, distinguishing patients whose tumors would be most responsive to immunotherapy. Additionally, elucidating patients with hypermethylated antigen processing genes might help identify those who would benefit from immunotherapy combined with adjuvant DNA hypomethylating agents or histone deacetylase inhibitors, as these agents were previously reported to recover HLA and TAP1/2 expression in cervical cancer cell lines, allowing them to be recognized by cytotoxic T cells (32, 33); both are currently in preclinical HGS EOC studies.…”

Section: Discussionmentioning

confidence: 99%

Tumor Hypomethylation at 6p21.3 Associates with Longer Time to Recurrence of High-Grade Serous Epithelial Ovarian Cancer

et al. 2014

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In order to reveal biological mechanisms underlying clinical outcome of high-grade serous (HGS) epithelial ovarian carcinomas (EOC), we evaluated the association between tumor epigenetic changes and time to recurrence. We assessed methylation at approximately 450,000 genome-wide CpGs in tumors of 337 Mayo Clinic patients. Semi-supervised clustering of discovery (n=168) and validation (n=169) sets was used to determine clinically relevant methylation classes. Clustering identified two methylation classes based on 60 informative CpGs, which differed in time to recurrence in the validation set (R versus L class, p =2.9×10−3, HR =0.52, 95% CI=0.34, 0.80). Follow-up analyses considered genome-wide tumor mRNA expression (n=104) and CD8 T cell infiltration (n=89) in patient subsets. Hypo-methylation of CpGs located in 6p21.3 in the R class associated with cis up-regulation of genes enriched in immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA), increased CD8 T-cell tumor infiltration (p=7.6 × 10−5), and trans regulation of genes in immune-related pathways (p=1.6 × 10−32). This is the most comprehensive assessment of clinical outcomes with regard to EOC tumor methylation to date. Collectively, these results suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for HGS EOC.

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“…To analyze the suppressor capacity of Ado on effector CTL function, CD8+ T-cells specific for the YMLDLQPETT peptide derived from the E7 HPV-16 protein were obtained using a method previously reported by our group [41]. A total of 1 × 10 6 CTLs were previously cultured for 3 h in the presence of synthetic Ado (500 µM) or with 20 µl of supernatants obtained from MSCs cultured for 5 h in presence of 5 mM AMP.…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions

Mora‐García¹,

García‐Rocha

Morales-Ramírez

et al. 2016

J Transl Med

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BackgroundIn recent years, immunomodulatory mechanisms of mesenchymal stem/stromal cells (MSCs) from bone marrow and other “classic” sources have been described. However, the phenotypic and functional properties of tumor MSCs are poorly understood. The aim of this study was to analyze the immunosuppressive capacity of cervical cancer-derived MSCs (CeCa-MSCs) on effector T lymphocytes through the purinergic pathway.MethodsWe determined the expression and functional activity of the membrane-associated ectonucleotidases CD39 and CD73 on CeCa-MSCs and normal cervical tissue-derived MSCs (NCx-MSCs). We also analyzed their immunosuppressive capacity to decrease proliferation, activation and effector cytotoxic T (CD8+) lymphocyte function through the generation of adenosine (Ado).ResultsWe detected that CeCa-MSCs express higher levels of CD39 and CD73 ectonucleotidases in cell membranes compared to NCx-MSCs, and that this feature was associated with the ability to strongly suppress the proliferation, activation and effector functions of cytotoxic T-cells through the generation of large amounts of Ado from the hydrolysis of ATP, ADP and AMP nucleotides.ConclusionsThis study suggests that CeCa-MSCs play an important role in the suppression of the anti-tumor immune response in CeCa through the purinergic pathway.

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Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid

Cited by 59 publications

References 42 publications

Analysis of Class I Major Histocompatibility Complex Gene Transcription in Human Tumors Caused by Human Papillomavirus Infection

Analysis of Class I Major Histocompatibility Complex Gene Transcription in Human Tumors Caused by Human Papillomavirus Infection

Tumor Hypomethylation at 6p21.3 Associates with Longer Time to Recurrence of High-Grade Serous Epithelial Ovarian Cancer

Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions

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