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Targeting of Human p53-overexpressing Tumor Cells by an HLA A*0201-restricted Murine T-Cell Receptor Expressed in Jurkat T Cells¹

Division of General and Oncologic Surgery [X. L., E. A. P., J. D. I. E.] and Department of Hematology Research [D. J. D.], Beckman Research Institute of the City of Hope and City of Hope National Medical Center, Duarte, California 91010

A potent anti-human (hu) p53 CD8⁺ CTL response develops in HLA A*0201 transgenic (Tg) mice after immunization with peptides corresponding to HLA A*0201 motifs from hu p53. Mice immunized with the hu p53_149–157 peptide develop a CTL response that is of moderately high affinity and is capable of recognizing hu tumor cells expressing mutated p53. In this report, the mRNAs encoding the predominantly expressed T-cell receptor (TCR) sequences were molecularly cloned from a murine (mu) CTL clone derived from immunized Tg mice, which recognized endogenously processed hu p53 restricted by HLA A*0201. The separate A and B chain TCR cDNAs were transfected in the corresponding TCR A^- and B^- Jurkat-CD3^- mutant T-cell lines, and each rescued CD3 surface expression. Both TCR chains were simultaneously introduced into Jurkat-CD3⁺ cells, and the transfected Jurkat cells recognized hu T2 cells sensitized with the p53_149–157 CTL epitope but not T2 cells sensitized with a nonspecific CTL epitope. Breast, pancreatic, and sarcoma tumor cell lines, which overexpress endogenous mutated p53, were recognized in the presence of anti-CD28 costimulation, only if they also expressed HLA A*0201. Normal hu fibroblasts established from skin cultures were not recognized. These results represent the first time that a p53-specific TCR capable of recognizing hu cancer cells was heterologously expressed in a naive recipient cell, converting that cell to one recognizing hu tumor cells with mutated p53. This TCR represents a candidate molecule for a genetic strategy in combating hu cancer by an adoptive immunotherapy approach, which uses the strong xenorecognition of hu p53 in mice.

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