Genetic Diversity of the KIR/HLA System and Outcome of Patients with Metastatic Colorectal Cancer Treated with Chemotherapy

Re, Vallì De; Caggiari, Laura; Zorzi, Mariangela De; Talamini, Renato; Racanelli, Vito; Andrea, Mario D’; Buonadonna, Angela; Zagonel, Vittorina; Cecchin, Erika; Innocenti, Federico; Toffoli, Giuseppe

doi:10.1371/journal.pone.0084940

Cited by 38 publications

(33 citation statements)

References 69 publications

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“…Other than the justification above, another justification is that the ligands of activating KIRs are not necessarily HLAs; rather, they are still unknown [36], [53]. This, can be pointed out as the limitation of the previous studies.…”

Section: Resultsmentioning

confidence: 98%

“…We know that the interaction KIR-HLA has two sides of KIR and HLA. For example overexpression of HLA-E on surface of colorectal cancer cells can result in inhibition of NKs [53] and such patients have better survival from the disease [54]; of course the receptor of HLA-E is CD94/NKG2a [55], [56]. KIR2DL1 and 2DS1 interact with HLA-C2, and KIR2DL2, 2DL3 and 2DS2 interact with HLA-C1 [57]; so every mathematical predict do not occur.…”

Section: Resultsmentioning

confidence: 99%

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Colorectal cancer and the KIR genes in the human genome: A meta-analysis

et al. 2016

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Colorectal cancer is one of the most common types of inflammation-based cancers and is occurred due to growth and spread of cancer cells in colon and/or rectum. Previously genetic association of cell cycle genes, both proto-oncogenes and the tumor suppressors has been proved. But there were few studies about association of immune related genes such as killer-cell immunoglobulin-like receptors (KIRs). Thus we intend to perform a meta-analysis to find the association of different genes of KIR and susceptibility to be affected by colorectal cancer. The overall population of the four studies investigated in our meta-analysis was 953 individuals (470 individuals with colorectal cancer and 483 individuals in control groups). After the analyses, we concluded that colorectal cancer is affected by KIR2DS5 and also there were no protecting gene. This result shows the inflammatory basis of this cancer. In other words, in contrast to leukemia and blood cancers, colorectal cancers seem to be affected by hyper activity of natural killer-cells (NKs). Whys and therefore of this paradox, is suggested to be investigated further.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Colorectal cancer and the KIR genes in the human genome: A meta-analysis

et al. 2016

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“…Most of these studies only explored the association between the presence of KIR/HLA frequencies in cancer with the aim to test the impact of KIR/HLA status on individual’s susceptibility (26). A recent study performed in patients with metastatic colon cancer demonstrated that the genotyping KIR/HLA pairs helps to predict overall survival to treatment with FOLFIRI (27). In the same context, the critical early role of NK cells in facilitating response to imatinib in patients with chronic phase-chronic myeloid leukemia (CP-CML) that cannot be overcome by subsequent intensification of therapy is well known.…”

Section: Discussionmentioning

confidence: 99%

KIR Genes and Their Ligands Predict the Response to Anti-EGFR Monoclonal Antibodies in Solid Tumors

et al. 2016

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Killer-cell immunoglobulin-like receptors (KIRs) regulate the killing function of natural killer cells, which play an important role in the antibody-dependent cell-mediated cytotoxicity response exerted by therapeutic monoclonal antibodies (mAbs). However, it is unknown whether the extensive genetic variability of KIR genes and/or their human leukocyte antigen (HLA) ligands might influence the response to these treatments. This study aimed to explore whether the variability in KIR/HLA genes may be associated with the variable response observed to mAbs based anti-epidermal growth factor receptor (EGFR) therapies. Thirty-nine patients treated with anti-EGFR mAbs (trastuzumab for advanced breast cancer, or cetuximab for advanced colorectal or advanced head and neck cancer) were included in the study. All the patients had progressed to mAbs therapy and were grouped into two categories taking into account time to treatment failure (TTF ≤6 and ≥10 months). KIR genotyping (16 genetic variability) was performed in genomic DNA from peripheral blood by PCR sequence-specific primer technique, and HLA ligand typing was performed for HLA-B and -C loci by reverse polymerase chain reaction sequence-specific oligonucleotide methodology. Subjects carrying the KIR/HLA ligand combinations KIR2DS1/HLAC2C2-C1C2 and KIR3DS1/HLABw4w4-w4w6 showed longer TTF than non-carriers counterparts (14.76 vs. 3.73 months, p < 0.001 and 14.93 vs. 4.6 months, p = 0.005, respectively). No other significant differences were observed. Two activating KIR/HLA ligand combinations predict better response of patients to anti-EGFR therapy. These findings increase the overall knowledge on the role of specific gene variants related to responsiveness to anti-EGFR treatment in solid tumors and highlight the importance of assessing gene polymorphisms related to cancer medications.

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“…Regarding malignant diseases, certain KIR/HLA types have been associated with the susceptibility or worse clinical outcome in several types of cancer, such as leukemia, colorectal cancer and lung cancer (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

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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Genetic Diversity of the KIR/HLA System and Outcome of Patients with Metastatic Colorectal Cancer Treated with Chemotherapy

Cited by 38 publications

References 69 publications

Colorectal cancer and the KIR genes in the human genome: A meta-analysis

Colorectal cancer and the KIR genes in the human genome: A meta-analysis

KIR Genes and Their Ligands Predict the Response to Anti-EGFR Monoclonal Antibodies in Solid Tumors

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

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