A peptide encoded by the human MAGE3 gene and presented by HLA-1344 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE3

Abstract

The human MAGE3 gene is expressed in a significant proportion of tumors of various histological types, but is silent in normal adult tissues other than testis and placenta. Antigens encoded by MAGE3 may therefore be useful targets for specific antitumor immunization. Two antigenic peptides encoded by the MAGE3 gene have been reported previously. One is presented to cytolytic T lymphocytes (CTL) by HLA-A1, the other by HLA-A2 molecules. Here we show that MAGE3 also codes for a peptide that is presented to CTL by HLA-B44. MAGE3 peptides containing the HLA-B44 peptide binding motif were synthesized. Peptide MEVDPIGHLY, which showed the strongest binding to HLA-B44, was used to stimulate blood T lymphocytes from normal HLA-B44 donors. CTL clones were obtained that recognized not only HLA-B44 cells sensitized with the peptide, but also HLA-B44 tumor cell lines expressing MAGE3. The proportion of metastatic melanomas expressing the MAGE3/HLA-B44 antigen should amount to approximately 17% in the Caucasian population, since 24% of individuals carry the HLA-B44 allele and 76% of these tumors express MAGE3.

Characterization of antigenic peptides presented by HLA-B44 molecules on tumor cells expressing the geneMAGE-3

“…Likewise, the amount of peptide needed for half-maximal lysis by this CTL line could not be determined. An M3-167 specific CTL clone, 346/8, has been obtained from a different, B*4403+ healthy donor LB822 (Herman et al, 1996). Here we independently confirmed that this clone specifically recognized M3-167/B*4403 complexes both on incubation of B*4403+/MAGE-3-target cells with synthetic peptide M3-167 and after endogenous processing in B*4403+ /MAGE-3+ melanoma cells (Fig.…”

“…CTLs specific for this peptide were able to rccognizeMAGE-3+ /HLA-B44' melanoma cells, indicating that M3-167 is naturally processed and presented by melanoma cells (Fig. 2 and Herman et al, 1996). This is further suggested by the observation that the amount of peptidc required for half-maximal lysis of peptide-pulsed target cells by CTL clone 346/8 is relatively low (Fig.…”

“…Furthermore, we showed here the results of a limited number of in vitro stimulation experiments. However, the number of CD8+ precursors that has to be screened to obtain one specific CTL for a given peptide may, particularly in unprimed donors, be higher than 2 X lo6, as used in the present study (Herman et al, 1996). A larger number of stimulations with a panel of several donors would, therefore, have to be performed to exclude a relevant antigenicity of the other peptides analyzed here.…”

Monoclonal antibody 57B stains tumor tissues that express geneMAGE-A4

“…Many antigenic peptides presented to CTL by HLA class I molecules have been identified in the MAGE-A proteins. For instance, five antigenic peptides, presented by HLA-A1, A2, A24, or B44 are derived from the MAGE-A3 protein, and one peptide presented by HLA-A2 is derived from MAGE-A4 (Celis et al, 1994;Gaugler et al, 1994;Herman et al, 1996;Tanaka et al, 1997;van der Bruggen et al, 1994).…”

MAGE-A is frequently expressed in triple negative breast cancer and associated with epithelial-mesenchymal transition

“…Cancer/testis antigens (CTA), a series of tumor associated antigens, are exclusively expressed in diverse tumor entities [15] but silent in normal tissues except for testicular germ cells and placenta [16][17][18]. Due to the restricted expression pattern and their capability to elicit immune responses, CTAs are counted as ideal targets for immunotherapy in human malignancy [19][20].…”