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. 2016 Feb 15;8(2):222-30.
doi: 10.4251/wjgo.v8.i2.222.

Evaluation of antibody-dependent cell-mediated cytotoxicity activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients

Cristiana Lo Nigro  1 , Vincenzo Ricci  1 , Daniela Vivenza  1 , Martino Monteverde  1 , Giuliana Strola  1 , Francesco Lucio  1 , Federica Tonissi  1 , Emanuela Miraglio  1 , Cristina Granetto  1 , Mirella Fortunato  1 , Marco Carlo Merlano  1
Affiliations

Evaluation of antibody-dependent cell-mediated cytotoxicity activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients

Cristiana Lo Nigro et al. World J Gastrointest Oncol. .

Abstract

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 (mCRC) patients treated with cetuximab.

Methods: Forty-one KRAS wt mCRC 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 lymphoprep-peripheral blood mononuclear cell and iNKT cells were defined by co-expression of CD3, TCRVα24, TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity, measuring lactate dehydrogenase release.

Results: 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 iNKT cells with OS (P = 0.19), albeit we observed a trend to a longer survival after 10 mo in patients with iNKT 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 FCGR2A and TT in FCGR3A presented a trend of longer PFS (median 9 vs 5 mo; P = 0.064). Chemotherapy impacted both iNKT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.

Conclusion: Our results suggest a link between iNKT cells, basal ADCC activity, genotypes in FCGR2A and FCGR3A, and efficacy of cetuximab in KRAS wt mCRC patients.

Keywords: Antibody-dependent cell-mediated cytotoxicity; Cetuximab; Invariant natural killer T cells; Metastatic colorectal cancer; RAS family; Single nucleotide polymorphism in Fc-γ receptors.

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Figures

Figure 1
Figure 1
Overall survival in 41 metastatic colorectal cancer treated with cetuximab in II and III lines according to median basal level of invariant natural killer T cells (0.382 cells/microliter). iNKT: Invariant natural killer T.
Figure 2
Figure 2
Overall survival in 41 metastatic colorectal cancer treated with cetuximab in II and III lines according to median basal level of antibody-dependent cell-mediated cytotoxicity activity (71%). ADCC: Antibody-dependent cell-mediated cytotoxicity.
Figure 3
Figure 3
Overall survival in 41 metastatic colorectal cancer patients stratified for both invariant natural killer T and antibody-dependent cell-mediated cytotoxicity activity at basal level, below and above the respective median level. iNKT = 0.382 cells/microliter; ADCC = 71%. iNKT: Invariant natural killer T; ADCC: Antibody-dependent cell-mediated cytotoxicity.
Figure 4
Figure 4
Progression free survival in compound heterozygote patients for single nucleotide polymorphisms rs1801274 in FCGR2A and rs396991 in FCGR3A genes in the 41 metastatic colorectal cancer patients.
Figure 5
Figure 5
Overall survival in 30 metastatic colorectal cancer patients with a blood drawn after 2 mo (A) and in 23 patients with a blood drawn after 4 mo of treatment (B). Analysis was done in 4 groups of patients: The first included patients showing both ADCC activities above the median level [ADCCbas above/II (or III) above, where II means on blood drawn after 2 mo and III after 4 mo], the second group a decrease from a basal above median to a II or III determination below median [ADCCbas above/II (or III) below], the third group patients showing instead an increase from below at basal and above at II or III determination [ADCCbas below/II (or III) above] and the fourth group patients with both ADCC activities below the median level [ADCCbas below/II (or III) below]. ADCC: Antibody-dependent cell-mediated cytotoxicity.
See this image and copyright information in PMC

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