Dr. Ferrone's presentation:
Chondroitin Sulphate Proteoglycan 4 (CSPG4), an Attractive Target of Antibody-based Immunotherapy in Various Types of Solid Tumors
SPEAKER
Dr. Soldano Ferrone
Professor, Massachusetts General Hospital, Harvard Medical School
ABSTRACT
Like CD44 (CSPG8), the tumor cell membrane-bound CSPG4, also known as high molecular weight-melanoma associated antigen (HMW-MAA), or neuron-glial antigen 2 (NG2), is a member of the CSPG family. CSPGs are key bioactive molecules that play a major role in tumor growth, migration and neo angiogenesis. CSPG4 is a unique glycoprotein-proteoglycan complex consisting of a 250 kDa N-linked glycoprotein and a 450 kDa proteoglycan component. It is composed of three major structural components: the extracellular domain (consisting of 3 subdomains), the transmembrane region, and the cytoplasmic C-terminal domain (CTD).
Flow cytometry analysis of established cancer cell lines stained with mAbs and immunohistochemical staining of surgically excised tumors from patients have shown that CSPG4 is expressed on glioma, squamous cell carcinoma of the head and neck (SCCHN), esophageal squamous cell carcinoma, triple negative breast cancer (TNBC), melanoma, mesothelioma, renal cell carcinoma, chordoma, chondrosarcoma, osteosarcoma, and soft tissue sarcomas. On most malignant cells CSPG4 has a high expression with limited intra- and inter-lesional heterogeneity. It is noteworthy that CSPG4 is expressed not only on differentiated malignant cells, but also on cancer initiating cells (CICs). Therefore targeting CSPG4 may eliminate not only differentiated cancer cells, but also CICs. In contrast CSPG4 has a restricted distribution in normal tissues. It is expressed on activated pericytes in the tumor microenvironment. As a result neo angiogenesis and growth of tumor cells, even those which do not express CSPG4 are inhibited.
The structural and functional properties of CSPG4 are highly conserved through phylogenetic evolution. The high degree of homology, but not complete identity among CSPG4s in various animal species accounts for their ability to overcome unresponsiveness to self-CSPG4 in xenogeneic hosts. This mechanism accounts for the ability of DNA encoding human CSPG4 in combination with electroporation to elicit humoral immunity to self-CSPG4 in dogs with melanoma. In agreement with results obtained in patients with melanoma immunized with CSPG4 mimics, this immunity appears to have clinical significance, since it is associated with a favorable clinical course of the disease.
Most, if not all the available CSPG4-specific mAb are not effective in mediating complement- and cell-dependent lysis of tumor cells. On the other hand, the few CSPG4-specific mAb used have been very useful to generate chimeric antigen receptors to redirect T cells to tumors expressing this tumor antigen. Furthermore CSPG4-specific mAbs are very effective in inhibiting both in vitro and in vivo signal transduction pathways associated with tumor cell proliferation, survival and migration. These results provide a mechanism(s) for the ability of CSPG4-specific mAbs to inhibit tumor growth, and more importantly disease recurrence and metastatic spread in immunodeficient mice grafted with human melanoma, TNBC or mesothelioma cells.
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