The immunoproteasome regulates a PRAME-derived HLA-I tumor antigen that can be targeted therapeutically with a TCR mimic antibody
Aaron Y Chang1,2, Ron S Gejman1,2, Ronald C Hendrickson1, Cheng Liu3, David A Scheinberg1,2*
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065; 2Weill Medical College of Cornell University, New York, New York, 10065; 3Eureka Therapeutics, Emeryville, CA 94608
Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen which is over-expressed in multiple cancers including melanoma, leukemia, and breast cancer. Its expression in healthy adult tissue is generally limited to the testes and ovaries, making PRAME an attractive tumor-selective target. After proteasomal processing, PRAME-derived peptides including PRAME300-309 is presented on the cell surface in the context of HLA-A*02:01 (HLA-A2) molecules, for recognition by cytotoxic T cells. Using Pr20, a monoclonal antibody which recognizes the PRAME300-309 peptide in complex with HLA-A2, we demonstrate that the peptide/HLA-A2 complex can be targeted therapeutically in leukemia xenograft models in vivo. Interestingly, PRAME expression alone is insufficient for substantial cell-surface presentation of PRAME300-309. PRAME300-309 was minimally detectable in several melanomas and solid tumors, but dramatically increased upon treatment with the pro-inflammatory cytokine IFNγ, largely mediated by induction of the immunoproteasome catalytic subunit β5i. Knockout of β5i in solid tumor cell lines led to decreased IFNγ-mediated PRAME300-309 presentation. Biochemical analysis revealed that the immunoproteasome mediated reduced internal destructive cleavages within the PRAME300-309 peptide and therefore yielded more potentially presentable peptides in vitro. Our data highlight the importance of proteasomal constitution in PRAME peptide-presentation and has broad implications on presentation of other tumor-associated antigens.
Credits: None available.
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