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

Abstract

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;...

The competitive endogenous RNA regulatory network reveals potential prognostic biomarkers for overall survival in hepatocellular carcinoma

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The association of HLA/KIR genes with non-small cell lung cancer (adenocarcinoma) in a Han Chinese population

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Elevated IL‑6/IL‑1Ra ratio as a prognostic biomarker of poor chemotherapy efficacy in Chinese patients with metastatic NSCLC, validated in a Caucasian patient cohort

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“…101192-9 in the Fudan University Shanghai Cancer Center Ethical committee register. (18). Patient recruitment lasted for 7 months and the patients were followed for OS and PFS during at least 2 years, with a median follow-up time of 28 months.…”