CSPG4 as a target of antibody-based immunotherapy for malignant mesothelioma.
OBJECTIVE
Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane chondroitin sulphate proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)-based immunotherapy for MM.


METHODS
We assayed adhesion, motility, invasiveness, wound-healing, apoptosis, and anchorage-independent growth of MM cells on cell cultures. CSPG4 expression and signaling was studied by immunoblotting. The growth of MM severe combined immunodeficient (SCID) mice xenografts induced by PPM-Mill cells, engineered to express the luciferase reporter gene, was monitored by imaging, upon treatment with CSPG4 mAb TP41.2. Animal toxicity and survival were assayed in both tumor inhibition and therapeutic experiments.


RESULTS
CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of ECM. Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of focal adhesion kinase (FAK) and AKT, reduced expression of cyclin D1 and apoptosis. Moreover, mAb TP41.2 significantly reduced MM cell motility, migration, and invasiveness, and inhibited MM growth in soft agar. In vivo, treatment with mAb TP41.2 prevented or inhibited the growth of MM xenografts in SCID mice, with a significant increase in animal survival.


CONCLUSIONS
These results establish the safety of CSPG4 mAb-based immunotherapy and suggest that CSPG4 mAb-based immunotherapy may represent a novel approach for the treatment of MM.
University of Hawai'i Cancer Center, HI, USA.
Zeyana
Z
Rivera
Soldano
S
Ferrone
Xinhui
X
Wang
Sandro
S
Jube
Haining
H
Yang
Harvey I
HI
Pass
Shreya
S
Kanodia
Giovanni
G
Gaudino
Michele
M
Carbone
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness / Q000276:immunology; D014183:Transplantation, Heterologous; D000099216:Chondroitin Sulfate Proteoglycan 4
D000911:Antibodies, Monoclonal; D011508:Chondroitin Sulfate Proteoglycans; D008565:Membrane Proteins; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4