The level of MHC class I expression on murine adenocarcinoma can change the antitumor effector mechanism of immunocytokine therapy
| Autor: | M, Imboden, K R, Murphy, A L, Rakhmilevich, Z C, Neal, R, Xiang, R A, Reisfeld, S D, Gillies, P M, Sondel |
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| Rok vydání: | 2001 |
| Předmět: |
Mice
Inbred BALB C Immunoconjugates Lung Neoplasms Antibodies Neoplasm Recombinant Fusion Proteins Antibody-Dependent Cell Cytotoxicity Dose-Response Relationship Immunologic H-2 Antigens Antibodies Monoclonal Adenocarcinoma Epithelial Cell Adhesion Molecule Lymphocyte Activation Up-Regulation Killer Cells Natural Mice Antigens Neoplasm Tumor Cells Cultured Animals Interleukin-2 Female Immunotherapy Cell Adhesion Molecules Spleen |
| Zdroj: | Cancer research. 61(4) |
| ISSN: | 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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