The level of MHC class I expression on murine adenocarcinoma can change the antitumor effector mechanism of immunocytokine therapy

The huKS1/4-IL2 fusion protein, directed against the human epithelial cell adhesion molecule (huEpCAM) has been shown to induce a strong CD8(+) T-cell -dependent, natural killer (NK) cell-independent, antitumor response in mic e bearing the huEp-CAM-transfected CT26 colon cancer CT26-EpCAM. Here we in vestigate the effectiveness of huKS1/4-IL2 against CT26-Ep21.6, a subclone of CT26-EpCAM, expressing low levels of MHC class I. bl vitro antibody-depe ndent cellular cytotoxicity (ADCC) assays in the presence of huKS1/4-IL2 de monstrate that murine NK cells from spleen and blood can kill CT26-Ep21.6 s ignificantly better then they kill CT26-EpCAM, NK-mediated ADCC of CT26-EpC AM can be enhanced by blocking the murine Mt cell-inhibitory receptor, Ly-4 9C, A potent in vivo antitumor effect was observed when BALB/c mice bearing experimental metastases of CT26-Ep21.6 were treated with huKS1/4-IL2, The depletion of NK cells during huKS1/4-IL2 treatment significantly reduced th e antitumor effect against CT26-Ep21.6. Together our in vitro and in vivo d ata in the huEp-CAM-transfected CT26 models indicate that the amount of MHC class I expressed on the tumor target cell plays a critical role in the in vivo antitumor mechanism of huKS1/4-IL2 immunotherapy, A low MHC class I l evel favors NK cells as effecters, whereas a high level of MHC class I favo rs T cells as effecters. Given the heterogeneity of MHC class I expression seen in human tumors and the prevailing T-cell suppression in many cancer p atients, the observation that huKS1/4-IL2 has the potential to effectively activate an NK cell-based antitumor response may be of potential clinical r elevance.