Expression of Potential Targets for Cell-Based Therapies on Melanoma Cells

Abstract

Tumor antigen-specific redirection of cytotoxic T cells (CTLs) or natural killer (NK) cells including chimeric antigen receptor (CAR-) and T cell receptor (TCR-) cell therapy is currently being evaluated in different tumor entities including melanoma. Expression of melanoma-specific antigen recognized by the respective CAR or TCR directly or presented by HLA molecules is an indispensable prerequisite for this innovative therapy. In this study, we investigated in 168 FFPE tumor specimens of patients with stage I-IV melanoma the protein expression of HER2, TRP2, ABCB5, gp100, p53, and GD2 by immunohistochemistry (IHC). These results were correlated with clinical parameters. Membrane expression of HER2 and GD2 was also investigated in ten melanoma cell lines by flow cytometry for which corresponding tumors were analyzed by IHC. Our results demonstrated that gp100 was the most frequently overexpressed protein (61%), followed by TRP2 (50%), GD2 (38%), p53 (37%), ABCB5 (17%), and HER2 (3%). TRP2 expression was higher in primary tumors compared to metastases (p = 0.005). Accordingly, TRP2 and ABCB5 expression was significantly associated with lower tumor thickness of the primary (p = 0.013 and p = 0.025). There was no association between protein expression levels and survival in advanced melanoma patients. Flow cytometric analysis revealed abundant surface expression of GD2 and HER2 in all melanoma cell lines. The discordant HER2 expression in situ and in vitro suggests a tissue culture associated induction. In summary, our data support the use of gp100 and GD2 as a potential target for developing engineered TCR- or CAR-cell therapies, respectively, against melanoma.

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment

“…Strobel S.B. et al observed HER2 overexpression in 3% of human primary melanomas [ 52 ]. However, all of the melanoma cell lines they tested uniformly expressed HER2.…”

CAR NK Cell Therapy for the Treatment of Metastatic Melanoma: Potential & Prospects

“…Pre-melanosome protein (PMEL; PMEL17; glycoprotein 100, gp100) ordinarily plays a role in melanin synthesis and is highly specific to melanoma [181]. Because PMEL is broadly overexpressed (61-90%) in melanoma patients [175,181,182], independent of their stage of disease progression, PMEL is of especially great interest as a therapeutic target. CAR-NK92MI cells bearing TCR-like CARs were assembled by selecting the TCR-like antibody GPA7 against the PMEL/HLA-A2 complex and then fused to the intracellular domain of a CD3-ζ chain [175].…”

The biological role and immunotherapy of gangliosides and GD3 synthase in cancers

“…Marx et al discovered that there was lower expression in the core of glioblastoma multiforme than in the margin of the tumor ( Marx et al, 2020 ). Melanomas express a large amount of GD2 that is widely distributed on the membrane of tumor cells and in the cytoplasm ( Strobel et al, 2021 ). Hersey et al detected that the expression of disialogangliosides GD2 was higher in metastatic melanomas than in primary melanomas, which revealed that the expression of GD2 was probably associated with the metastatic potential of the tumor ( Hersey et al, 1988 ).…”