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

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

doi:10.1371/journal.pone.0084940

Abstract

ObjectiveTo explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).MethodsA total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.ResultsFor CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.ConclusionThis study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.

Highlights

The innate immune system is the first line of defense in response to tumor cell
We developed a killer-cell immunoglobulin-like receptors (KIR)/human leucocyte antigen (HLA) pair genotyping to characterize the spectrum of Natural Killer (NK)-related immune genes in CRC response to FOLFIRI treatment in univariate and multivariate analysis
HLA-Bw4-I80 was associated with improved complete response (CR) rates (CR versus PR+SD+PD) with Odds ratios (OR) ranging from 2.1 to 4.3 (p,0.05, Table 2)

Summary

Introduction

The innate immune system is the first line of defense in response to tumor cell. Natural Killer (NK) cells perform an important role in this response with their ability to kill tumor cells, produce cytokines, and cross-talk with the adaptive system. Interactions between killer-cell immunoglobulin-like receptors (KIR)-receptors and human leucocyte antigen (HLA)-ligand regulate the response of NK cells, resulting in a multitude of KIR/HLA combinations and different NK effects. Modification of tumor-cell due to chemotherapeutic-treatment may contribute to a difference in NK-response. Immunotherapy aimed at enhancing natural antitumor T-cell immunity in patients affected by advanced malignancies are currently being implemented in the clinic with promising results, often showing a synergic effect with chemotherapy [3]. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, acknowledgement of the exact mechanisms that modulate action of the host immunity resulting in an effect on patient outcome are not entirely clear and Characteristics

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Conclusion