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Evaluation of antibody-dependent cell-mediatedcy totoxicity activity and cetuximab response in KRAS wildtype metastatic colorectal cancer patients

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World Journal of Gastrointestinal Oncology 2016年第2期8卷 222-230页

作者： cristiana lo nigro vincenzo ricci daniela vivenza martino monteverde giuliana strola francesco lucio federica tonissi emanuela miraglio cristina granetto mirella fortunato marco carlo merlano laboratory of cancer genetics and translational oncology oncology departments.croce and carle teaching hospital12100 Cuneo Italy medical oncology oncology departments.croce and carle teaching hospital12100 Cuneo Italy laboratory department s.croce and carle teaching hospital12100 Cuneo Italy radiotherapy department s.croce and carle teaching hospital12100 Cuneo Italy pathology department s.croce and carle teaching hospital12100 Cuneo Italy

AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with ***: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase ***: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of ***: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.

关键词： Metastatic colorectal cancer Single nucleotidepolymorphism in Fc-γ receptors Cetuximab RAS family Antibody-dependent cell-mediated cytotoxicity invariantnatural killer T cells

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