HLA and Killer Immunoglobulin-like Receptor Genes as Outcome Predictors of Hepatitis C Virus–Related Hepatocellular Carcinoma

Cariani, Elisabetta; Pilli, Massimo; Zerbini, Alessandro; Rota, Cristina; Olivani, Andrea; Zanelli, Paola; Zanetti, Adele; Trenti, Tommaso; Ferrari, Carlo; Missale, Gabriele

doi:10.1158/1078-0432.ccr-13-0986

Cited by 47 publications

(44 citation statements)

References 35 publications

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“…At univariate analysis, OS of patients was influenced by age at diagnosis, Child-Pugh score and type of treatment, as already reported, 14 but was independent of clinical parameters such as nodule number, size and BCLC, that have been identified as major determinants of HCC outcome, 16 and of the frequency of total circulating T and NK-cells. Among clinical parameters, only Child-Pugh score was associated with TTR.…”

Section: Discussionsupporting

confidence: 64%

“…Previous reports have shown the involvement of activating NKG2D-mediated signaling in the immune response toward HCC, 11,12 and loss of expression of NKG2D ligand ULBP1 upon tumor progression has been related to early recurrence after surgical resection. 11 In a recent study, we identified a relationship between better HCC prognosis and KIR2DS5, HLA-C1 and compound KIR2DL2-C1/ KIR3DS1-Bw4T80 genotypes, 14 supported by increased cytotoxic capacity of NKcells from subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3. NK-cell receptor signaling is also involved in the functional regulation by the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 94%

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Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

et al. 2016

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(controls) were phenotypically characterized. Unsupervised clustering based on the frequency of cells expressing different phenotypic NK-cell markers segregated HCC patients into different cohorts that were compared for outcome. NK-cell cytokine production and cytotoxicity were compared between cohorts with different overall survival (OS) and time to disease recurrence (TTR). By multivariate analysis, age, Child-Pugh class and NK-cell phenotypic clustering could independently identify patients with significantly different OS. NK-cells from patients with better outcome expressed higher levels of cytotoxic granules and CD3z and lower levels of natural cytotoxic receptors (NCRs) that were co-expressed with the inhibitory receptor NKG2A known to negatively regulate NCR function. Cytotoxic function and IFNg production were significantly lower in the cohort of patients with worse outcome compared to controls (p < 0.05). Our results show a role for NK-cells in the control of HCC progression and survival providing the basis for the development of immunotherapeutic strategies to potentiate NK-cell response.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 94%

Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

et al. 2016

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“…In consideration of the clinicopathological variables, we observed that HLA-Bw4T80 was the only HLA type significantly affecting OS in multivariate analyses following multitest correction. This observation is consistent with a previous report (29), which suggested an association of HLA-Bw4T80 with decreased OS in patients with HCC. HLA-Bw4T80 is an allotype of the HLA-Bw4 motif with a threonine at position 80, which exhibits lower affinity for KIR3DL1 compared with the HLA-Bw4 motif with an isoleucine at the same position (30).…”

Section: Discussionsupporting

confidence: 94%

Typing of killer-cell immunoglobulin-like receptors and their cognate human leukocyte antigen class I ligands predicts survival of Chinese Han patients with metastatic non-small-cell lung cancer

Liu

Sansas

et al. 2016

Molecular and Clinical Oncology

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Abstract. Non-small-cell lung cancer (NSCLC) may establish an immunosuppressive tumor microenvironment that is conducive to tumor growth. Natural killer (NK) cells play a pivotal role in immunological surveillance. Activation of NK cells partially depends on the interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. We herein investigated the association of KIRs and HLA ligands with survival in metastatic NSCLC (mNSCLC) patients treated with chemotherapy in a Chinese Han population. Polymerase chain reaction with sequence-specific primers was used to type 15 KIRs at the DNA and mRNA level and 6 HLA ligands in 70 mNSCLC patients. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression model was applied for multivariate survival analysis, with the stepwise selection, to determine independent predictors of survival. It was observed that patients with KIR2DS4del gene expression at the mRNA level or HLA-Bw4T80 exhibited poor overall survival (OS). The multivariate analysis revealed that HLA-Bw4T80 and KIR2DS4del expression were independent predictors of OS. This observation indicated that the KIR/HLA ligand is a promising predictor of survival in mNSCLC and may also provide a strategy for treatment stratification and patient management. IntroductionNon-small-cell lung cancer (NSCLC) may establish an immunosuppressive tumor microenvironment that is conducive to tumor growth (1). Natural killer (NK) cells play a pivotal role in innate immunity and immunological surveillance (2). Activation of NK cells partly depends on the interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands (3). KIRs are a family of cell surface receptors expressed by NK cells and certain subpopulations of T lymphocytes. The KIR family consists of inhibitory as well as activating receptors characterized by both allelic (high numbers of variants) and haplotypic (different numbers of genes for inhibitory and activating receptors on individual chromosomes) polymorphisms (4). The ligands of KIRs are specific epitopes on HLA class I molecules (5). HLA-C allotypes fall into the C1 or C2 groups (asparagine and lysine, respectively, at position 80) that are recognized by KIR2DL2/KIR2DL3 and KIR2DL1/KIR2DS1, respectively. Two previous studies have implicated HLA-C1 and HLA-C2 as potential ligands for KIR2DS4 (6,7). KIR3DL1/KIR3DS1 recognizes HLA-Bw4 epitopes of HLA-A and HLA-B alleles, which are classified according to whether isoleucine or threonine is present at position 80 (4).An increased understanding of the complexities of the biology of the KIR/HLA system has provided opportunities to leverage NK cell function as a novel avenue of immunotherapy for cancer (8 HLA, human leukocyte antigen; NK, natural killer; NSCLC, non-small-cell lung cancer; mNSCLC, metastatic non-small-cell lung cancer; SSP-PCR, sequence-specific primer polymerase chain reaction;...

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“…The B group of haplotypes contains genes associated with chronic HCV infection and poor treatment response, including KIR2DL2 and KIR2DS2, but has a minor protective role against end stage manifestations including cirrhosis and HCC, possibly through the activation of NK cells leading to stellate cell apoptosis in the case of fibrosis 39, 40, 41, 42. Activating KIR, components of the KIR B haplotypes, have been previously shown to have a beneficial effect against HCC development 42. We found no other association between genes which influence viral clearance and disease progression.…”

Section: Discussionmentioning

confidence: 99%

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

et al. 2015

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Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)‐λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA‐C1C1 (P = 0.027), IFN‐λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA‐B (TapG:HLA‐B114D) (P = 0.007) and HLA‐DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN‐λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA‐C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non‐interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.

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HLA and Killer Immunoglobulin-like Receptor Genes as Outcome Predictors of Hepatitis C Virus–Related Hepatocellular Carcinoma

Cited by 47 publications

References 35 publications

Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments

Typing of killer-cell immunoglobulin-like receptors and their cognate human leukocyte antigen class I ligands predicts survival of Chinese Han patients with metastatic non-small-cell lung cancer

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

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