Immunological consequences of antibody-tumor antigen interactions on the development of potent anti-tumor immunity

The efficacy of cancer vaccines is limited by the endogenous nature of most clinically relevant tumor antigens, as they are perceived by the immune system as self-molecules. HER-2/neu-transgenic mice ( neu-N), which overexpress the non-transforming rat HER-2/neu protein and recognize the neu antigen as an endogenous molecule, are among the most clinically relevant models for testing strategies for preventing and treating cancer. Neu-targeted vaccination alone is not capable of eradicating neu-expressing tumors in this model. However, the incorporation of neu-specific murine monoclonal antibodies (mAb) with neu-targeted vaccination enhances tumor elimination in neu-N mice. In addition, even though three different neu-specific murine mAbs (7.9.5, 7.16.4, 7.21.2) can mediate antibody-dependent cellular cytotoxicity (ADCC), this does not appear to be the primary mechanism by which these mAbs enhance the vaccine-induced antitumor response. Carrageenan (a macrophage inhibiting agent), not anti-asialoGM-1 antibody (an NK cell inhibiting agent), abrogates the mAb enhancement most potently. Moreover, 7.16.4, the murine analogue of Trastuzumab, localizes at the neu vaccine site within 48 hours, and its Fc portion is necessary for mediating this enhanced vaccine-induced antitumor response. These data all together suggest that antigen presenting cells (APCs) in particular dendritic cells (DCs) play a key role in the mAb-mediated enhancement of vaccine-induced antitumor response. Further experiments show that the 7.16.4 plus neu vaccine treatment dramatically increases the vaccine cell-uptake by DCs. In addition, the mechanism of increased uptake is Fc receptor-mediated, and likely enhances antigen cross-priming by DCs. This increase in the number of DCs with phagocytosed vaccine cells in turn leads to greater neu-specific CD8+ T cell proliferation, activation, and memory development. In conclusion, the 7.16.4 plus neu vaccine treatment enhances the overall immune repertoire of neu-specific CD8 + T cells, resulting in a significantly potent antitumor response against neu-overexpressing tumor in neu-N mice. Therefore, this study sheds light on the clinical applicability of combining mAb with vaccine and vice versa, since such treatment modality may help overcome immune tolerance to self-tumor antigens and weaken the immunosuppressive network in cancer patients. These findings also instruct us as to possible mechanisms for engineering mAbs for improved clinical efficacy.