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Article

Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients

1
Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan
2
Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto 390-8621, Nagano, Japan
3
Department of Life Innovation, Shinshu University, Matsumoto 390-8621, Nagano, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Paola Vacca, Laura Chiossone and Emanuela Marcenaro
Cancers 2021, 13(13), 3267; https://doi.org/10.3390/cancers13133267
Received: 20 April 2021 / Revised: 21 June 2021 / Accepted: 25 June 2021 / Published: 29 June 2021
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
Natural killer (NK) cells normally respond to tumor cells and virally infected cells by killing them via the innate immune system. However, the functional impairment of NK cells has been observed in hepatocellular carcinoma. The NK-cell phenotype is partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This study evaluated the involvement of KIR–HLA pairs in hepatocellular carcinoma development in 211 patients with hepatitis C virus-associated cirrhosis. HLA-Bw4 and the KIR3DL1+HLA-Bw4 pair were significantly associated with hepatocellular carcinoma onset during a median follow-up of 6.6 years, which suggested that functional interactions between KIR and HLA or HLA-Bw4 may influence the risk of cancer development.
Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset. View Full-Text
Keywords: cirrhosis; hepatitis C virus; hepatocellular carcinoma; human leukocyte antigen; killer cell immunoglobulin-like receptors; natural killer cells cirrhosis; hepatitis C virus; hepatocellular carcinoma; human leukocyte antigen; killer cell immunoglobulin-like receptors; natural killer cells
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MDPI and ACS Style

Umemura, T.; Joshita, S.; Saito, H.; Wakabayashi, S.-i.; Kobayashi, H.; Yamashita, Y.; Sugiura, A.; Yamazaki, T.; Ota, M. Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients. Cancers 2021, 13, 3267. https://doi.org/10.3390/cancers13133267

AMA Style

Umemura T, Joshita S, Saito H, Wakabayashi S-i, Kobayashi H, Yamashita Y, Sugiura A, Yamazaki T, Ota M. Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients. Cancers. 2021; 13(13):3267. https://doi.org/10.3390/cancers13133267

Chicago/Turabian Style

Umemura, Takeji, Satoru Joshita, Hiromi Saito, Shun-ichi Wakabayashi, Hiroyuki Kobayashi, Yuki Yamashita, Ayumi Sugiura, Tomoo Yamazaki, and Masao Ota. 2021. "Investigation of the Effect of KIR–HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients" Cancers 13, no. 13: 3267. https://doi.org/10.3390/cancers13133267

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