Abstract
We have investigated the possibility of inducing cytotoxic T lymphocytes (CTL) to Ras containing a mutation at position 61 or to normal Ras, using recombinant vaccinia viruses expressing these proteins. CTL from C57Bl/10 mice immunized with vaccinia expressing mutant Ras showed specificity for the mutant Ras protein and recognition of normal Ras was inefficient. The opposite specificity was observed after immunization with vaccinia expressing normal Ras, since CTL isolated from these mice recognized normal Ras well and mutant Ras inefficiently. Levels of endogenous Ras expression were insufficient for lysis by these CTL. One CTL epitope mapped to amino acids 60-67 and residue 61 was critical for T cell recognition. CTL generated against mutant Ras protein recognized peptide 60-67 containing mutant residue 61, while anti-normal Ras CTL recognized the wild-type 60-67 sequence. A second epitope mapped to residues 152-159 of Ras and was recognized equally well by CTL raised to normal or mutant Ras. The murine data raise the possibility of exploiting Ras-specific CTL for targeted immunotherapy of certain human cancers.
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- Andrew M. E., Coupar B. E., Boyle D. B., Blanden R. V. Recognition by major histocompatibility complex class I-restricted cytolytic T lymphocytes of cells expressing vaccinia-encoded viral and class I proteins. Eur J Immunol. 1987 Oct;17(10):1515–1518. doi: 10.1002/eji.1830171021. [DOI] [PubMed] [Google Scholar]
- Anichini A., Fossati G., Parmiani G. Clonal analysis of cytotoxic T-lymphocyte response to autologous human metastatic melanoma. Int J Cancer. 1985 May 15;35(5):683–689. doi: 10.1002/ijc.2910350518. [DOI] [PubMed] [Google Scholar]
- Aosai F., Ohlen C., Ljunggren H. G., Höglund P., Franksson L., Ploegh H., Townsend A., Kärre K., Stauss H. J. Different types of allospecific CTL clones identified by their ability to recognize peptide loading-defective target cells. Eur J Immunol. 1991 Nov;21(11):2767–2774. doi: 10.1002/eji.1830211118. [DOI] [PubMed] [Google Scholar]
- Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
- Bishop J. M. Molecular themes in oncogenesis. Cell. 1991 Jan 25;64(2):235–248. doi: 10.1016/0092-8674(91)90636-d. [DOI] [PubMed] [Google Scholar]
- Braciale T. J., Braciale V. L. Antigen presentation: structural themes and functional variations. Immunol Today. 1991 Apr;12(4):124–129. doi: 10.1016/0167-5699(91)90096-C. [DOI] [PubMed] [Google Scholar]
- Capon D. J., Seeburg P. H., McGrath J. P., Hayflick J. S., Edman U., Levinson A. D., Goeddel D. V. Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations. Nature. 1983 Aug 11;304(5926):507–513. doi: 10.1038/304507a0. [DOI] [PubMed] [Google Scholar]
- Chakrabarti S., Brechling K., Moss B. Vaccinia virus expression vector: coexpression of beta-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol. 1985 Dec;5(12):3403–3409. doi: 10.1128/mcb.5.12.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chang E. H., Furth M. E., Scolnick E. M., Lowy D. R. Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus. Nature. 1982 Jun 10;297(5866):479–483. doi: 10.1038/297479a0. [DOI] [PubMed] [Google Scholar]
- Cobbold S. P., Jayasuriya A., Nash A., Prospero T. D., Waldmann H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature. 1984 Dec 6;312(5994):548–551. doi: 10.1038/312548a0. [DOI] [PubMed] [Google Scholar]
- Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
- Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
- Fujita J., Srivastava S. K., Kraus M. H., Rhim J. S., Tronick S. R., Aaronson S. A. Frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3849–3853. doi: 10.1073/pnas.82.11.3849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- GORER P. A. Studies in antibody response of mice to tumour inoculation. Br J Cancer. 1950 Dec;4(4):372–379. doi: 10.1038/bjc.1950.36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gedde-Dahl T., 3rd, Eriksen J. A., Thorsby E., Gaudernack G. T-cell responses against products of oncogenes: generation and characterization of human T-cell clones specific for p21 ras-derived synthetic peptides. Hum Immunol. 1992 Apr;33(4):266–274. doi: 10.1016/0198-8859(92)90334-j. [DOI] [PubMed] [Google Scholar]
- Gedde-Dahl T., 3rd, Spurkland A., Eriksen J. A., Thorsby E., Gaudernack G. Memory T cells of a patient with follicular thyroid carcinoma recognize peptides derived from mutated p21 ras (Gln-->Leu61). Int Immunol. 1992 Nov;4(11):1331–1337. doi: 10.1093/intimm/4.11.1331. [DOI] [PubMed] [Google Scholar]
- Guerrero I., Villasante A., Corces V., Pellicer A. Loss of the normal N-ras allele in a mouse thymic lymphoma induced by a chemical carcinogen. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7810–7814. doi: 10.1073/pnas.82.23.7810. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hämmerling G. J., Rüsch E., Tada N., Kimura S., Hämmerling U. Localization of allodeterminants on H-2Kb antigens determined with monoclonal antibodies and H-2 mutant mice. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4737–4741. doi: 10.1073/pnas.79.15.4737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hérin M., Lemoine C., Weynants P., Vessière F., Van Pel A., Knuth A., Devos R., Boon T. Production of stable cytolytic T-cell clones directed against autologous human melanoma. Int J Cancer. 1987 Mar 15;39(3):390–396. doi: 10.1002/ijc.2910390320. [DOI] [PubMed] [Google Scholar]
- Itoh K., Platsoucas C. D., Balch C. M. Autologous tumor-specific cytotoxic T lymphocytes in the infiltrate of human metastatic melanomas. Activation by interleukin 2 and autologous tumor cells, and involvement of the T cell receptor. J Exp Med. 1988 Oct 1;168(4):1419–1441. doi: 10.1084/jem.168.4.1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jung S., Schluesener H. J. Human T lymphocytes recognize a peptide of single point-mutated, oncogenic ras proteins. J Exp Med. 1991 Jan 1;173(1):273–276. doi: 10.1084/jem.173.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koszinowski U. H., Reddehase M. J., Keil G. M., Volkmer H., Jonjic S., Messerle M., del Val M., Mutter W., Münch K., Bühler B. Molecular analysis of herpesviral gene products recognized by protective cytolytic T lymphocytes. Immunol Lett. 1987 Dec;16(3-4):185–192. doi: 10.1016/0165-2478(87)90146-5. [DOI] [PubMed] [Google Scholar]
- Ljunggren H. G., Kärre K. Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. J Exp Med. 1985 Dec 1;162(6):1745–1759. doi: 10.1084/jem.162.6.1745. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ljunggren H. G., Stam N. J., Ohlén C., Neefjes J. J., Höglund P., Heemels M. T., Bastin J., Schumacher T. N., Townsend A., Kärre K. Empty MHC class I molecules come out in the cold. Nature. 1990 Aug 2;346(6283):476–480. doi: 10.1038/346476a0. [DOI] [PubMed] [Google Scholar]
- Monaco J. J. A molecular model of MHC class-I-restricted antigen processing. Immunol Today. 1992 May;13(5):173–179. doi: 10.1016/0167-5699(92)90122-N. [DOI] [PubMed] [Google Scholar]
- Rosenberg S. A., Lotze M. T., Muul L. M., Chang A. E., Avis F. P., Leitman S., Linehan W. M., Robertson C. N., Lee R. E., Rubin J. T. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987 Apr 9;316(15):889–897. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
- Stauss H. J., Davies H., Sadovnikova E., Chain B., Horowitz N., Sinclair C. Induction of cytotoxic T lymphocytes with peptides in vitro: identification of candidate T-cell epitopes in human papilloma virus. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):7871–7875. doi: 10.1073/pnas.89.17.7871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
- Taparowsky E., Suard Y., Fasano O., Shimizu K., Goldfarb M., Wigler M. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature. 1982 Dec 23;300(5894):762–765. doi: 10.1038/300762a0. [DOI] [PubMed] [Google Scholar]
- Townsend A., Ohlén C., Bastin J., Ljunggren H. G., Foster L., Kärre K. Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nature. 1989 Aug 10;340(6233):443–448. doi: 10.1038/340443a0. [DOI] [PubMed] [Google Scholar]
- Van Pel A., De Plaen E., Boon T. Selection of highly transfectable variant from mouse mastocytoma P815. Somat Cell Mol Genet. 1985 Sep;11(5):467–475. doi: 10.1007/BF01534840. [DOI] [PubMed] [Google Scholar]
- Zarling J. M., Eichberg J. W., Moran P. A., McClure J., Sridhar P., Hu S. L. Proliferative and cytotoxic T cells to AIDS virus glycoproteins in chimpanzees immunized with a recombinant vaccinia virus expressing AIDS virus envelope glycoproteins. J Immunol. 1987 Aug 15;139(4):988–990. [PubMed] [Google Scholar]
- de Vries J. E., Spits H. Cloned human cytotoxic T lymphocyte (CTL) lines reactive with autologous melanoma cells. I. In vitro generation, isolation, and analysis to phenotype and specificity. J Immunol. 1984 Jan;132(1):510–519. [PubMed] [Google Scholar]
- van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991 Dec 13;254(5038):1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]