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 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.
Liu
X
X
Division of General and Oncologic Surgery, Beckman Research Institute of the City of Hope and City of Hope National Medical Center, Duarte, California 91010, USA.
Peralta
E A
EA
Ellenhorn
J D
JD
Diamond
D J
DJ
D000818:Animals; D003001:Cloning, Molecular; D015234:HLA-A Antigens / Q000502:physiology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
D015234:HLA-A Antigens; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53