CSPG4: a prototype oncoantigen for translational immunotherapy studies

Abstract

Thanks to striking progress in both the understanding of anti-tumor immune response and the characterization of several tumor associated antigens (TAA), a more rational design and more sophisticated strategies for anti-tumor vaccination have been possible. However, the effectiveness of cancer vaccines in clinical trial is still partial, indicating that additional studies are needed to optimize their design and their pre-clinical testing. Indeed, anti-tumor vaccination success relies on the choice of the best TAA to be targeted and on the translational power of the pre-clinical model used to assess its efficacy. The chondroitin sulfate proteoglycan-4 (CSPG4) is a cell surface proteoglycan overexpressed in a huge range of human and canine neoplastic lesions by tumor cells, tumor microenvironment and cancer initiating cells. CSPG4 plays a central role in the oncogenic pathways required for malignant progression and metastatization. Thanks to these features and to its poor expression in adult healthy tissues, CSPG4 represents an ideal oncoantigen and thus an attractive target for anti-tumor immunotherapy. In this review we explore the potential of CSPG4 immune-targeting. Moreover, since it has been clearly demonstrated that spontaneous canine tumors mimic the progression of human malignancies better than any other pre-clinical model available so far, we reported also our results indicating that CSPG4 DNA vaccination is safe and effective in significantly increasing the survival of canine melanoma patients. Therefore, anti-CSPG4 vaccination strategy could have a substantial impact for the treatment of the wider population of spontaneous CSPG4-positive tumor affected dogs with a priceless translational value and a revolutionary implication for human oncological patients.

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

“…Early strategies targeting CSPG4 utilized the development of anti-idiotypic antibodies (anti-id), which target the binding sites of other anti-CSPG4 antibodies, essentially mimicking the tumor antigen’s binding site on the antibody, and thus aiming to serve as immunogens or vaccines ( 91 , 92 ). A clinical study reported increased survival and metastasis regression in patients with melanoma who developed anti-CSPG4 antibodies following administration of the anti-idiotypic mAb MK2-23 ( 93 ).…”

Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma

“…Systemic chemotherapy has yielded controversial and quite disappointing results and recently, attention has been focused on the role of the immune system resulting in the development of two immunotherapeutic approaches, namely a xenogeneic DNA vaccine against human tyrosinase (Oncept, Merial), and a CSPG4-immunotargeting vaccine. 1 Despite a significant improvement in treatment during the last years, canine MM continues to represent a major clinical challenge.…”

“…Regardless of the anatomical location, complete surgical resection associated with regional lymphadenectomy and/or radiotherapy is the preferred treatment modality. Systemic chemotherapy has yielded controversial and quite disappointing results and recently, attention has been focused on the role of the immune system resulting in the development of two immunotherapeutic approaches, namely a xenogeneic DNA vaccine against human tyrosinase (Oncept, Merial), and a CSPG4‐immunotargeting vaccine …”

Strengths and Weaknesses of Pre-Clinical Models for Human Melanoma Treatment: Dawn of Dogs’ Revolution for Immunotherapy

“…As a step in this direction, we focused our attention on one of the most interesting MAA identified so far, the chondroitin sulfate proteoglycan 4 (CSPG4). It is a prototype “oncoantigen” in human melanomas, since it has a restricted expression in healthy/normal tissues, but a high expression on melanoma cells in almost 85% of patients [ 150 , 151 ]. The CSPG4 has a key role in regulating the proliferative, migratory, invasive and metastatizing ability of cancer cells and their chemoresistance, therefore simultaneously regulating several processes needed for cancer development and progression.…”

“…On these bases, we identified CSPG4 as a new marker for canine patients affected by spontaneous oral melanoma [ 151 , 152 ]. We performed two veterinary trials to evaluate the potential of a xenogeneic DNA vaccine coding for the human CSPG4 in canine melanoma patients affected by spontaneous stage II-III CSPG4-positive oral melanomas.…”