Abstract
BackgroundActivity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown.MethodsWe assessed immune cells infiltrate (CD56, CD68, CD3, CD4, CD8, Foxp3) in the primary tumor of metastatic colorectal cancer (mCRC) patients treated with a first-line cetuximab-based chemotherapy in the framework of prospective trials (treatment group) and in a matched group of mCRC patients who received the same chemotherapy regimen without cetuximab (control group). The relationship between intra-tumoral immune effector cells, the K-ras status and the efficacy of the treatment were investigated. We also evaluated in vitro, the ADCC activity in healthy donors and chemonaive mCRC patients and the specific contribution of CD56+ cells.ResultsADCC activity against DLD1 CRC cell line is maintained in cancer patients and significantly declined after CD56+ cells depletion. In multivariate analysis, K-ras wild-type (HR: 4.7 (95% CI 1.8-12.3), p = 0.001) and tumor infiltrating CD56+ cells (HR: 2.6, (95%CI:1.14-6.0), p = 0.019) were independent favourable prognostic factors for PFS and response only in the cetuximab treatment group. By contrast CD56+ cells failed to predict PFS and response in the control group.ConclusionsCD56+ cells, mainly NK cells, may be the major effector of ADCC related-cetuximab activity. Assessment of CD56+ cells infiltrate in primary colorectal adenocarcinoma may provide additional information to K-ras status in predicting response and PFS in mCRC patients treated with first-line cetuximab-based chemotherapy.
Highlights
Activity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects
Based on the potential value of Antibody-dependent cell-mediated cytotoxicity (ADCC) in cetuximab activity, we assessed in metastatic colorectal cancer (mCRC) patients, the role of peripheral blood mononuclear cells (PBMC) and their CD56+ subpopulation in ADCC activity and we evaluated the relationship between the intratumoral immune cells and the efficacy of first-line cetuximab-based chemotherapy
The two groups were similar regarding all variables matched including the proportion of patients treated with the FOLFIRI
Summary
A chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. The activity of cetuximab has largely been attributed to the direct antiproliferative and proapoptotic effects of the antibody Another possible mechanism of its antitumor effects is mediated through antibody-dependent cell-mediated cytotoxicity (ADCC). The ADCC mediated through Fc receptors (FcγR) carried by NK cells, macrophages and polymorphonuclear leukocytes, is a well-recognized immune effector mechanism in the antitumor effect of IgG1 [17]. Of these cells, NK cells represent the principal ADCC effector cells [18,19]. Tregs can inhibit the function of dendritic cells, NK cells, B cells and other immune cells [23,24,25] and alter ADCC activity
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