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 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.
Department of Human Ontology, University of Wisconsin-Madison, 53792, USA.
M
M
Imboden
K R
KR
Murphy
A L
AL
Rakhmilevich
Z C
ZC
Neal
R
R
Xiang
R A
RA
Reisfeld
S D
SD
Gillies
P M
PM
Sondel
D000230:Adenocarcinoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006183:H-2 Antigens / Q000096:biosynthesis / Q000276:immunology*; D018796:Immunoconjugates / Q000276:immunology* / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D006183:H-2 Antigens; D018796:Immunoconjugates; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins