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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-02, Vol.61 (4), p.1500-1507
• Main Authors: IMBODEN, Michael, MURPHY, Kristopher R, RAKHMILEVICH, Alexander L, NEAL, Zane C, RONG XIANG, REISFELD, Ralph A, GILLIES, Stephen D, SONDEL, Paul M
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - secondary; Adenocarcinoma - therapy; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Neoplasm - biosynthesis; Antibody-Dependent Cell Cytotoxicity - immunology; Antigens, Neoplasm - immunology; Antineoplastic agents; Biological and medical sciences; Cell Adhesion Molecules - immunology; Dose-Response Relationship, Immunologic; Epithelial Cell Adhesion Molecule; Female; H-2 Antigens - biosynthesis; H-2 Antigens - immunology; Immunoconjugates - immunology; Immunoconjugates - pharmacology; Immunotherapy; Immunotherapy - methods; Interleukin-2 - immunology; Interleukin-2 - pharmacology; Killer Cells, Natural - immunology; Lung Neoplasms - immunology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Lymphocyte Activation - immunology; Medical sciences; Mice; Mice, Inbred BALB C; Pharmacology. Drug treatments; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacology; Spleen - cytology; Spleen - immunology; Tumor Cells, Cultured; Up-Regulation
• ISSN: 0008-5472; 1538-7445

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 mice bearing the huEp-CAM-transfected CT26 colon cancer CT26-EpCAM. Here we investigate the effectiveness of huKS1/4-IL2 against CT26-Ep21.6, a subclone of CT26-EpCAM, expressing low levels of MHC class I. In vitro antibody-dependent cellular cytotoxicity (ADCC) assays in the presence of huKS1/4-IL2 demonstrate that murine NK cells from spleen and blood can kill CT26-Ep21.6 significantly better than they kill CT26-EpCAM. NK-mediated ADCC of CT26-EpCAM can be enhanced by blocking the murine NK cell-inhibitory receptor, Ly-49C. 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 the antitumor effect against CT26-Ep21.6. Together our in vitro and in vivo data 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 level favors NK cells as effectors, whereas a high level of MHC class I favors T cells as effectors. Given the heterogeneity of MHC class I expression seen in human tumors and the prevailing T-cell suppression in many cancer patients, the observation that huKS1/4-IL2 has the potential to effectively activate an NK cell-based antitumor response may be of potential clinical relevance.