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Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing¹

Jon A. Weidanz^2,*,, Tiffany Nguyen, Tito Woodburn, Francisca A. Neethling, Maurizio Chiriva-Internati, William H. Hildebrand and Joseph Lustgarten^¶

^* Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106; Receptor Logic, Ltd., Amarillo, TX 79106; Department of Microbiology and Immunology, Texas Tech University Health Sciences Center, Lubbock, TX 79430; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and ^¶ Sidney Kimmel Cancer Center, San Diego CA 92121

Recognition of tumor-associated Ags (TAAs) on tumor cells by CTLs and the subsequent tumor cell death are assumed to be dependent on TAA protein expression and to correlate directly with the level of peptide displayed in the binding site of the HLA class I molecule. In this study we evaluated whether the levels of Her-2/neu protein expression on human tumor cell lines directly correlate with HLA-A*0201/Her2/neu peptide presentation and CTL recognition. We developed a TCR mimic (TCRm) mAb designated 1B8 that specifically recognizes the HLA-A2.1/Her2/neu peptide (369–377) (Her2₍₃₆₉₎-A2) complex. TCRm mAb staining intensity varied for the five human tumor cell lines analyzed, suggesting quantitative differences in levels of the Her2₍₃₆₉₎-A2 complex on these cells. Analysis of tumor cell lines pretreated with IFN- and TNF- for Her2/neu protein and HLA-A2 molecule expression did not reveal a direct correlation between the levels of Her2/neu Ag, HLA-A2 molecule, and Her2₍₃₆₉₎-A2 complex expression. However, compared with untreated cells, cytokine-treated cell lines showed an increase in Her2₍₃₆₉₎-A2 epitope density that directly correlated with enhanced tumor cell death (p = 0.05). Although a trend was observed between tumor cell lysis and the level of the Her2₍₃₆₉₎-A2 complex for untreated cells, the association was not significant. These findings suggest that tumor cell susceptibility to CTL-mediated lysis may be predicted based on the level of specific peptide-MHC class I expression rather than on the total level of TAA expression. Further, these studies demonstrate the potential of the TCRm mAb for validation of endogenous HLA-peptide epitopes on tumor cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Advanced Technology Program National Institute of Standards and Technology Grant 70NANB4H3048.

² Address correspondence and reprint requests to Dr. Jon A. Weidanz, Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, TX 79106. E-mail address: jon.weidanz{at}ttuhsc.edu

³ Abbreviations used in this paper: TAA, tumor-associated Ag; p369, aa 369–377 from He2/neu; TCRm, TCR mimic; MFI, mean fluorescence intensity; MFIR, MFI ratio.

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