Targeting of human p53-overexpressing tumor cells by an HLA A*0201-restricted murine T-cell receptor expressed in Jurkat T cells

A potent anti-human (hu) p53 CD8(+) CTL response develops in HLA A*0201 tra nsgenic (Tg) mice after immunization with peptides corresponding to HLA A*0 201 motifs from hu p53. Mice immunized with the hu p53(149-157) peptide dev elop a CTL response that is of moderately high affinity and is capable of r ecognizing 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) CTI, clone derived from immunized Tg mice, which recognized endogenously processed hu p53 restricted by HLA A*02 01, The separate A and B chain TCR cDNAs were transfected in the correspond ing TCR A(-) and B- Jurkat-CD3(-) mutant T-cell lines, and each rescued CD3 surface expression, Both TCR chains were simultaneously introduced into Ju rkat-CD3(+) cells, and the transfected Jurkat cells recognized hu T2 cells sensitized with the p53(149-157) CTL epitope hut not T2 cells sensitized wi th a nonspecific CTL epitope, Breast, pancreatic, and sarcoma tumor cell li nes, which overexpress endogenous mutated p53, were recognized in the prese nce of anti-CD28 costimulation, only if they also expressed HLA A*0201. Nor mal hu fibroblasts established from skin cultures were not recognized. Thes e results represent the first time that a p53-specific TCR capable of recog nizing hu cancer cells was heterologously expressed in a naive recipient ce ll, converting that cell to one recognizing hu tumor cells with mutated p53 . This TCR represents a candidate molecule for a genetic strategy in combat ing hu cancer by an adoptive immunotherapy approach, which uses the strong xenorecognition of hu p53 in mice.