Chondroitin Sulfate Proteoglycan 4 and Its Potential As an Antibody Immunotherapy Target across Different Tumor Types

Abstract

Overexpression of the chondroitin sulfate proteoglycan 4 (CSPG4) has been associated with the pathology of multiple types of such as melanoma, breast cancer, squamous cell carcinoma, mesothelioma, neuroblastoma, adult and pediatric sarcomas, and some hematological cancers. CSPG4 has been reported to exhibit a role in the growth and survival as well as in the spreading and metastasis of tumor cells. CSPG4 is overexpressed in several malignant diseases, while it is thought to have restricted and low expression in normal tissues. Thus, CSPG4 has become the target of numerous anticancer treatment approaches, including monoclonal antibody-based therapies. This study reviews key potential anti-CSPG4 antibody and immune-based therapies and examines their direct antiproliferative/metastatic and immune activating mechanisms of action.

Keywords: CSPG4; HMW-MAA; MCSP; NG2; antibodies; immunotherapy; melanoma; triple-negative breast cancer.

Figure 1

Structure and functions of chondroitin sulfate proteoglycan 4 (CSPG4) and antibody-based treatment approaches. (A) Schematic representation of CSPG4 proposed structure and functions in cancer. CSPG4 has three extracellular domains: D1, D2 and D3. Domain 1 (D1) consists of two laminin G like domains (L1 and L2) proposed to interact with the extracellular matrix (ECM). Domain 2 (D2) consists of 15 CSPG repeats containing chondroitin sulfate chain decoration. It is proposed to interact with integrins and ECM proteins, and to bind and present growth factors to receptor tyrosine kinases. Domain 3 (D3) contains putative protease cleaving sites and may be involved in protein shedding. The cytoplasmic tail containing proline- and threonine-rich sites, is thought to interact with different proteins and function as a phosphoacceptor site for the extracellular signal-regulated kinase 1/2 (ERK1/2), respectively. The PDZ domain is involved in protein scaffolding functions. CSPG4 is therefore implicated in cellular signaling pathways, including the mitogen-activated protein kinase pathway, through the receptor tyrosine kinase-ERK1/2 axis and the focal adhesion kinase (FAK) pathway, through the ECM–fibronectin–integrin axis. These may promote survival, proliferation and migration, cytoskeletal reorganization that may promote motility, invasiveness, and angiogenesis. (B) Key cancer antibody immunotherapy strategies targeting CSPG4: 1. Classic antibody approaches, functioning through two mechanisms—direct blockade of cell signaling functions and antibody dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP) mediated by immune effector cells like macrophages and NK cells; 2. Combination of CSPG4 blocking antibodies and BRAF inhibitors; 3. Cytolytic fusion proteins (CFPs); 4. Bispecific T cell engager antibodies (BiTEs) redirecting cytotoxic T cells toward CSPG4 overexpressing cells; 5. Chimeric antigen receptor (CAR) T cells, redirecting genetically modified T cells toward CSPG4 overexpressing cells.