Parihar R, Dierksheide J, Hu Y, Carson WEIL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells. J Clin Invest 110: 983-992

Department of Molecular Virology, Immunology, and Medical Genetics, The Arthur G. James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 11/2002; 110(7):983-92. DOI: 10.1172/JCI15950
Source: PubMed


The anti-tumor activity of recombinant mAb's directed against tumor cell growth receptors has generally been considered to result from direct antiproliferative effects, the induction of apoptosis, or possibly Ab-dependent cellular cytotoxicity mediated against tumor targets. However, it remains unclear to what degree these mechanisms actually aid in the clearance of Ab-coated tumor cells in vivo. We show here that NK cells secrete a distinct profile of potent immunostimulatory cytokines in response to dual stimulation with Ab-coated tumor cells and IL-12. This response could not be duplicated by costimulation with other ILs and was significantly enhanced in the presence of monocytes. Cytokine production was dependent upon synergistic signals mediated by the activating receptor for the Fc portion of IgG (FcgammaRIII) and the IL-12 receptor expressed on NK cells. Coadministration of Ab-coated tumor cells and IL-12 to BALB/c mice resulted in enhanced circulating levels of NK cell-derived cytokines with the capacity to augment anti-tumor immunity. These findings suggest that, in addition to mediating cellular cytotoxicity and apoptosis, the anti-tumor activity of mAb's might also result from activation of a potent cytokine secretion program within immune effectors capable of recognizing mAb-coated targets.

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    • "In this study rhIL-12 was given subcutaneously and was well tolerated but trial was terminated before completion due to low response rates in the rhIL-12 arm. More recent preclinical studies have highlighted the potential for IL-12 to costimulate NK cell IFN-γ production in combination with antitumor monoclonal antibodies [105, 113, 114]. These findings have been translated into several phase 1 and 2 clinical trials of IL-12 administered in concert with antitumor monoclonal antibodies in head and neck carcinoma [115, 116] and lymphoma [117]. "
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    • "There is evidence supporting a role for trastuzumab in mediating ADCC [95]. The interaction between the Fc domain of trastuzumab and FcR on effecter cells has shown major ADCC involvement and IL-12 enhances cytotoxicity against mAb-coated tumor cells [96, 97]. NK cytotoxicity via ADCC is probably one of the mechanisms of action of trastuzumab, but its mode of action includes CDC and complement-dependent cell-mediated cytotoxicity [98, 99]. "
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    • "In vitro, this process is termed as ADCC. Laboratory studies have shown that HER2-overexpressing breast cancer cell lines are susceptible to ADCC in the presence of trastuzumab (Carson et al, 2001; Parihar et al, 2002; Gennari et al, 2004), and in vivo activity of trastuzumab has been correlated with significantly increased number of peritumoral lymphocytes and monocytes and in vitro ADCC (Gennari et al, 2004; Arnould et al, 2006). Additional studies have indicated that NK cells are keys for trastuzumab-mediated ADCC (Cooley et al, 1999; Clynes et al, 2000; Mimura et al, 2005). "
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