Melanoma‐associated chondroitin sulphate proteoglycan as a new target antigen for CD4⁺ T cells in melanoma patients

Abstract

Melanoma-associated chondroitin sulfate proteoglycan (MCSP) (also known as high molecular weight-melanoma-associated antigen) represents an interesting target antigen for cancer immunotherapy which is expressed on human melanomas and other tumors such as breast carcinomas, gliomas, neuroblastomas and acute leukemias. MCSP seems to play an important functional role in melanoma as it is involved in tumor cell migration, invasion and angiogenesis. In this study, we isolated CD4 1 T helper cells from the blood of a healthy donor, recognizing a peptide from the MCSP core protein presented by HLA-DBR1*1101 molecules. T cell reactivity against the identified peptide could be detected in the blood of healthy donors and melanoma patients. MCSP specific T cells from the blood of a patient could be readily expanded by repeated peptide stimulation and recognized MCSP and HLA-DR expressing tumor cells. Our findings suggest that vaccination against MCSP helper T cell epitopes might be a promising approach to fight melanoma. ' 2008 Wiley-Liss, Inc. Key words: MCSP; melanoma; peptide; T helper cells; tumor antigenFollowing the identification of tumor-associated antigens recognized by T cells on human tumor cells, numerous clinical vaccination studies have been performed in patients with metastatic melanoma. Accompanied by an improvement of vaccine approaches including new adjuvants such as CpG oligonucleotides and further development in the field of immuno-monitoring, the induction of antigen-specific T cell responses in the blood of tumor patients has been demonstrated in a number of studies. However, significant tumor regressions, especially complete responses in patients with visceral metastases have been observed infrequently, and in most studies overall response rates did not exceed 10%. 1 One obstacle might be immune escape by downregulation or complete loss of antigen expression as many antigens identified so far do not play an essential functional role for the tumor. [2][3][4] To overcome this it would be particularly important to choose a suitable target antigen for vaccination therapy, which should be broadly expressed and functionally relevant for the tumor. On our search for suitable target antigens for the active-specific immunotherapy of melanoma, we focused on the human melanoma-associated chondroitin sulfate proteoglycan (MCSP), also known as high molecular weight-melanoma-associated antigen, which has been shown to be expressed in the majority of human melanoma lesions and cultured cells with a limited expression in normal tissues. 5,6 In addition, MCSP expression was found in uveal melanoma, which is refractory to standard chemotherapy. 7 MCSP represents an unique glycoprotein-proteoglycan complex, with a 250 kDa core glycoprotein to which, via serine residues, the larger than 450 kDa proteoglycan component is attached. 8 MCSP has been implicated for some time in numerous aspects of melanoma cell biology, including adhesion, spreading and migration. In fact, melanoma cell adhesion, chemotactic responses to fi...

CSPG4: a prototype oncoantigen for translational immunotherapy studies

“…Importantly, these peptide-specific CD4 + T cells could strongly recognize CSPG4 expressing melanoma cells, suggesting that the identified peptides are naturally processed by tumor cells. These findings supported the idea that the activation and the expansion of CSPG4-reactive CD4 + T cells circulating in the blood could be considered for further development of anti-CSPG4 immunotherapeutic strategies [91, 92]. …”

CSPG4 in Cancer: Multiple Roles

“…First, CSPG4 can be targeted with mAb, as shown in this study, as well as with T cells [50][51][52], thereby providing the opportunity to combine mAb-and T cell-based immunotherapeutic strategies. This combinatorial therapeutic strategy is expected to be able to counteract some of the escape mechanisms utilized by tumor cells to avoid recognition and destruction by the host immune system.…”

Cancer Stem Cell Markers in Head and Neck Squamous Cell Carcinoma

“…BMP-4 is thought to play roles in both cancer progression and inhibition in numerous human tumours [119, 165–182]. Chondroitin sulfate proteoglycan 4 (CSPG4) is a unique glycoprotein-proteoglycan complex that has been implicated in numerous aspects of melanoma cell biology and carcinoma (including HNSCC) with usefulness as a CSC in glioblastoma [183–189]. CXCR4 is a chemokine receptor that has been suggested to contribute to the metastasis of several cancers and has been found to be overexpressed in metastatic HNSCC [190–197].…”