A peptide encoded by human gene MAGE‐3 and presented by HLA‐A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE‐3

Abstract

The human MAGE-3 gene is expressed in many tumors of several histological types but it is silent in normal tissues, with the exception of testis. Antigens encoded by MAGE-3 may, therefore, be useful targets for specific anti-tumor immunization of cancer patients. We reported previously that MAGE-3 codes for an antigenic peptide recognized on a melanoma cell line by autologous cytolytic T lymphocytes (CTL) restricted by HLA-A1. Here we report that the MAGE-3 gene also codes for another antigenic peptide that is recognized by CTL restricted by HLA-A2. MAGE-3 peptides bearing consensus anchor residues for HLA-A2 were synthesized and tested for binding. T lymphocytes from normal individuals were stimulated with autologous irradiated lymphoblasts pulsed with each of three peptides that showed strong binding to HLA-A2. Peptide FLWGPRALV was able to induce CTL. We obtained CTL clones that recognized not only HLA-A2 cells pulsed with this peptide but also HLA-A2 tumor cell lines expressing the MAGE-3 gene. The proportion of melanoma tumors expressing this antigen should be approximately 32% in Caucasian populations, since 49% of individuals carry the HLA-A2 allele and 65% of melanomas express MAGE-3.

Mage-3 and Influenza-Matrix Peptide-Specific Cytotoxic T Cells Are Inducible in Terminal Stage HLA-A2.1+ Melanoma Patients by Mature Monocyte-Derived Dendritic Cells

“…In a previous study in advanced stage IV melanoma, we observed an expansion of specific CTL precursors for a defined MAGE-3 tumor peptide presented on HLA-A1 in long term culture assays (6). Here we have extended the study in a different group of patients to a MAGE-3 peptide (10) and an influenza matrix (IM) control peptide presented on HLA-A2.1. Enhancement of Ag-specific memory T cells was demonstrated by recall CTL and MHC tetramer binding assays following in vitro restimulation.…”

An optimum anti-melanoma response in mice immunized with fibroblasts transfected with DNA from mouse melanoma cells requires the expression of both syngeneic and allogeneic MHC-determinants

“…The products of genes that specify TAAs expressed by melanoma cells, such as BAGE, GAGE-1, MAGE-1, MAGE-2, MAGE-3, gp100 and tyrosinase, among others, have been identified as the targets of CTLs. [5][6][7][8][9][10][11][12][13] It is likely that these TAAs are only several representations of an undefined, and possibly large number of TAAs expressed by different cells that comprise the malignant cell population. Genetic instability is a characteristic phenotype of cancer cells.…”

Poxvirus as a vector to transduce human dendritic cells for immunotherapy: abortive infection but reduced APC function

“…In addition, the CTL resulting from such protocols have a good in vitro capacity for killing peptidepulsed target cells but only a modest capacity for killing tumor cells. 8 Alternatively, DC can be transduced to express full-length TAA genes. Physical methods of transfection such as DNA/liposome complexes or elec- selectively reduced the surface expression of the costimulatory molecule CD80 and the DC maturation marker CD83 on mature DC while other surface molecules including CD86 and MHC remained unchanged.…”