Effect of treatment resistance on CSPG4+ expression in metastatic melanoma across multiple treatment lines.

Abstract

e21540 Background: Immune checkpoint inhibitors (ICIs) and targeted therapies have improved outcomes in metastatic melanoma, but resistance remains a major challenge. Only 50% of patients achieve long-term disease control with ICIs, while most develop resistance to BRAF/MEK inhibitors. Cross-resistance to immunotherapy limits further options, including tumor-infiltrating lymphocyte (TIL) therapy. CSPG4, a cell surface molecule overexpressed in melanoma and minimally expressed in normal tissues, has shown promise as a CAR-T therapy target in preclinical models. We investigated whether CSPG4 expression persists in patients with metastatic melanoma following resistance to multiple treatment lines. Methods: We analyzed clinical and biological data from patients with melanoma treated between 2014 and 2024. Primary, metastatic and matched tumour samples (pre- and post-treatment with BRAF/MEK inhibitors and/or ICIs), obtained from Auria Biobank and from the Istituto Oncologico della Svizzera Italiana (IOSI) underwent CSPG4 immunohistochemistry (IHC). Results: Forty-six samples were analyzed, 31 from IOSI and 15 from Auria. All matched samples obtained before and after systemic treatment were CSPG4 positive, with a different intensity of IHC signal and pattern. In gene expression analysis, CSPG4 levels were 1.25-fold higher in metastases compared to primary tumors and 16.18-fold higher compared to normal tissue. CSPG4 was expressed in 83% of the 206 biobank samples, with the highest levels in primary tumors (97%) and skin metastases (94%) and lower levels in lymph node or distant metastases (73%). In 46 paired samples from patients with BRAF-mutated melanoma, CSPG4 expression was maintained after treatment with BRAF/MEK inhibitors, ICIs, or both, regardless of tissue origin or treatment received. Conclusions: CSPG4 expression is conserved in metastatic melanoma cells even after resistance to targeted therapies and ICIs, supporting its potential as a therapeutic target. These findings provide a strong rationale for the clinical development of CSPG4-directed therapies to address treatment resistance in melanoma.