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Inherent transcriptional signatures of NK cells are associated with response to IFNα + rivabirin therapy in patients with Hepatitis C Virus.

Ascierto ML, Bozzano F, Bedognetti D, Marras F, Schechterly C, Matsuura K, Picciotto A, Marenco S, Zhao Y, DeGiorgi V, Sommariva M, Moretta L, Wang E, Alter HJ, Marincola FM, De Maria A - J Transl Med (2015)

Bottom Line: In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D.A complex relationship was observed that suggested for extensive post-transcriptional editing.Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV.

Methods: To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment.

Results: The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection.

Conclusions: Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

No MeSH data available.


Related in: MedlinePlus

The SVR: NR gene set transcriptional profile is validated in independent cohorts of HCV patients. A) PCA analysis performed on the independent group of patients by using the 476 genes associated with treatment response in the training set of patients; B) PCA analysis performed on 8 treatment naïve chronically infected HCV patients (CH-HCV) by using the 476-transcript signature segregated the CH-HCV patients according a SVR-like and NR-like. Because of the high heterogeneity of NK profile derived from NR-like patients, the PCA was conducted by adding a centroid for each group of patients. C) The expression of NKp30 and NKG2D was evaluated on purified NK cells showing to be higher in NR-like patients as previously reported to occur for NR patients [29,34].
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Fig4: The SVR: NR gene set transcriptional profile is validated in independent cohorts of HCV patients. A) PCA analysis performed on the independent group of patients by using the 476 genes associated with treatment response in the training set of patients; B) PCA analysis performed on 8 treatment naïve chronically infected HCV patients (CH-HCV) by using the 476-transcript signature segregated the CH-HCV patients according a SVR-like and NR-like. Because of the high heterogeneity of NK profile derived from NR-like patients, the PCA was conducted by adding a centroid for each group of patients. C) The expression of NKp30 and NKG2D was evaluated on purified NK cells showing to be higher in NR-like patients as previously reported to occur for NR patients [29,34].

Mentions: We therefore studied whether the 476 gene-signature set identified in NK cells from NR vs. SVR patients would also segregate in chronically infected patients followed independently in another cohort of patients. To this end, independent gene expression analysis was performed on purified NK cells from PBMCs derived from 5 NR and 5 SVR patients from University of Genoa, Italy. Samples were obtained prior to treatment with PEG-IFN/RBV. PCA analysis was performed on this validating group of patients by using the 476 transcripts identified in the training set of patients, and confirmed that this gene set could efficiently differentiate SVR from NR patients in an independent cohort (Figure 4A).Figure 4


Inherent transcriptional signatures of NK cells are associated with response to IFNα + rivabirin therapy in patients with Hepatitis C Virus.

Ascierto ML, Bozzano F, Bedognetti D, Marras F, Schechterly C, Matsuura K, Picciotto A, Marenco S, Zhao Y, DeGiorgi V, Sommariva M, Moretta L, Wang E, Alter HJ, Marincola FM, De Maria A - J Transl Med (2015)

The SVR: NR gene set transcriptional profile is validated in independent cohorts of HCV patients. A) PCA analysis performed on the independent group of patients by using the 476 genes associated with treatment response in the training set of patients; B) PCA analysis performed on 8 treatment naïve chronically infected HCV patients (CH-HCV) by using the 476-transcript signature segregated the CH-HCV patients according a SVR-like and NR-like. Because of the high heterogeneity of NK profile derived from NR-like patients, the PCA was conducted by adding a centroid for each group of patients. C) The expression of NKp30 and NKG2D was evaluated on purified NK cells showing to be higher in NR-like patients as previously reported to occur for NR patients [29,34].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4353456&req=5

Fig4: The SVR: NR gene set transcriptional profile is validated in independent cohorts of HCV patients. A) PCA analysis performed on the independent group of patients by using the 476 genes associated with treatment response in the training set of patients; B) PCA analysis performed on 8 treatment naïve chronically infected HCV patients (CH-HCV) by using the 476-transcript signature segregated the CH-HCV patients according a SVR-like and NR-like. Because of the high heterogeneity of NK profile derived from NR-like patients, the PCA was conducted by adding a centroid for each group of patients. C) The expression of NKp30 and NKG2D was evaluated on purified NK cells showing to be higher in NR-like patients as previously reported to occur for NR patients [29,34].
Mentions: We therefore studied whether the 476 gene-signature set identified in NK cells from NR vs. SVR patients would also segregate in chronically infected patients followed independently in another cohort of patients. To this end, independent gene expression analysis was performed on purified NK cells from PBMCs derived from 5 NR and 5 SVR patients from University of Genoa, Italy. Samples were obtained prior to treatment with PEG-IFN/RBV. PCA analysis was performed on this validating group of patients by using the 476 transcripts identified in the training set of patients, and confirmed that this gene set could efficiently differentiate SVR from NR patients in an independent cohort (Figure 4A).Figure 4

Bottom Line: In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D.A complex relationship was observed that suggested for extensive post-transcriptional editing.Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV.

Methods: To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment.

Results: The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection.

Conclusions: Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.

No MeSH data available.


Related in: MedlinePlus