Targeting of HLA-DR molecules transduces agonistic functional signals in cutaneous melanoma.
The role of human leukocyte antigens (HLA) class II molecules in transducing intracellular signals in immune cells is well established. Solid tumors of different histotype can also express HLA class II antigens; however, their intracellular signaling ability is essentially unknown. Due to the frequent expression of HLA class II molecules in primary and metastatic lesions, cutaneous melanoma was utilized to investigate whether the engagement of HLA-DR molecules transduces functional intracellular signal(s). Triggering of HLA-DR molecules by the anti-HLA-DR monoclonal antibody (mAb) L243 induced a significant (P < 0.05) and dose-dependent growth-inhibition of metastatic melanoma cells Mel 120, as well as their homotypic aggregation. Furthermore, an increase in tyrosine phosphorylation of multiple cellular proteins with a molecular weight ranging from 66 to 130 kD, including p125 focal adhesion kinase, was observed. Lastly, the engagement of HLA-DR molecules by mAb L243 inhibited activator protein-1-DNA binding. Thus, HLA-DR molecules expressed on melanoma cells can transduce functional intracellular signals. This finding is consistent with evidences obtained in hematological malignancies, and suggests the potential usefulness of HLA-DR molecules to set-up new approaches of targeted therapy in metastatic melanoma.
Altomonte
Maresa
M
Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy. maltomonte@cro.it
Visintin
Alberto
A
Tecce
Raffaele
R
Leonardi
Antonio
A
Calabro
Luana
L
Fonsatti
Ester
E
Pucillo
Carlo
C
Maio
Michele
M
D000911:Antibodies, Monoclonal / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology*; D015153:Blotting, Western; D002449:Cell Aggregation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D004591:Electrophoresis, Polyacrylamide Gel; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008970:Molecular Weight; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D006684:HLA-DR Antigens; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human