| Treatment with a monoclonal antibody (mAb) to HER2 (trastuzumab) is now the standard of care for patients with HER2-overexpressing breast cancer, however, only 25-30% of patients will respond to this form of therapy. The anti-tumor actions of trastuzumab have generally been attributed to the inhibition of tumor cell proliferation or the induction of apoptosis. However, recent studies have shown that the anti-tumor effects of trastuzumab are dependent on immune cells that express receptors for the constant (Fc) region of immunoglobulin G. Natural killer (NK) cells are innate immune cells that express an activating Fc receptor (FcgammaRIIIa), which allows them to recognize and interact with Ab-coated targets. We proposed that the immune response to anti-tumor mAbs could be enhanced via the co-administration of NK cell-activating adjuvants. NK cells co-stimulated with trastuzumab-coated breast cancer cells and interleukin-12 (IL-12) secreted >10-fold higher amounts of interferon-gamma (IFN-gamma) as compared to NK cells stimulated with either agent alone. Co-stimulated NK cells also secreted abundant quantities of a number of chemokines that could induce the chemotaxis of naive and activated T cells. We detected elevated levels of IFN-gamma and T cell-recruiting chemokines within the sera of human cancer patients receiving trastuzumab and IL-12. These factors were functional for T cell chemotaxis and their presence correlated with the infiltration of tumor tissue by cytolytic CD8+ T cells. Furthermore, administration of IL-12 enhanced the actions of an anti-HER2 mAb in a murine model of HER2-positive cancer, an effect that was dependent on NK cell production of IFN-gamma and on the presence of CD8+ T cells. These results suggest that the anti-tumor effects of trastuzumab are mediated through the secretion of IFN-gamma and T cell-recruiting chemokines by activated NK cells, leading to the invasion and destruction of tumor tissue by cytolytic CD8+ T cells. Furthermore, these results suggest that administration of NK cell-activating adjuvants such as IL-12 could enhance the efficacy of trastuzumab by promoting NK cell production of these factors. |
