Immunotherapy of melanoma targeting human high molecular weight melanoma-associated antigen: potential role of nonimmunological mechanisms.
Induction of humoral anti-human high molecular weight melanoma-associated antigen (anti-HMW-MAA) immunity following active specific immunotherapy is associated with a statistically significant prolongation of survival in patients with melanoma. This association does not appear to be mediated by immunological mechanisms because anti-HMW-MAA antibodies are poor mediators of complement- and cell-mediated cytotoxicity of melanoma cells. Therefore, we have been investigating nonimmunological mechanisms by which anti-HMW-MAA antibodies (Abs) affect the biology of melanoma cells. We have demonstrated that anti-HMW-MAA mAbs interfere with the interaction of HMW-MAA with extracellular matrix (ECM) components, a process known to be crucial in the early phase of melanoma metastasis. Furthermore, anti-HMW-MAA mAbs appear to block the series of signal transduction events triggered by the interaction of HMW-MAA with ECM. They include the activation of the family of Rho GTPases, p130cas, and focal adhesion kinase (FAK). These findings parallel the inhibition of the rat homologue of HMW-MAA NG2 function by anti-NG2 antibodies. Taken together, all these results provide a mechanistic explanation not only for the therapeutic effect of anti-HMW-MAA antibodies in the treatment of melanoma, but also for the function of HMW-MAA in the biology of melanoma cells. This information is expected to serve as a useful background to design effective HMW-MAA-targeted immunotherapy in patients with melanoma.
Chang
Chien-Chung
CC
Department of Immunology, Roswell Park, Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Campoli
Michael
M
Luo
Wei
W
Zhao
Wanzhou
W
Zaenker
Kurt S
KS
Ferrone
Soldano
S
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry*; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D013997:Time Factors; D000099216:Chondroitin Sulfate Proteoglycan 4
D000951:Antigens, Neoplasm; D050719:Crk-Associated Substrate Protein; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D000099216:Chondroitin Sulfate Proteoglycan 4; C493841:BCAR1 protein, human; C496050:PTK2 protein, human