This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karanikas, V. Articles by Coulie, P. G. Search for Related Content PubMed PubMed Citation Articles by Karanikas, V. Articles by Coulie, P. G.

High Frequency of Cytolytic T Lymphocytes Directed against a Tumor-specific Mutated Antigen Detectable with HLA Tetramers in the Blood of a Lung Carcinoma Patient with Long Survival¹

Cellular Genetics Unit [V.K., J-F.B, R.C., J.T., I.G-R., C.G., T.B., P.G.C.], and Biochemistry Unit [E.V.S.], Université de Louvain, B-1200 Brussels; Ludwig Institute for Cancer Research, Brussels Branch, B-1200 Brussels [D.C., P.W., T.B.]; and Service de Pneumologie et d’Anatomopathologie, Hôpital de Mont-Godinne, Université de Louvain, B-5530 Yvoir [P.W.], Belgium

We have identified an antigen recognized by autologous CTL on the lung carcinoma cells of a patient who enjoyed a favorable clinical evolution, being alive 10 years after partial resection of the primary tumor. The antigenic peptide is presented by HLA-A2 molecules and encoded by a mutated sequence in the gene coding for malic enzyme, an essential enzyme that converts malate to pyruvate. In the tumor cell line derived from the patient, only the mutated malic enzyme allele is expressed, because of a loss of heterozygosity in the region of chromosome 6 that contains this locus. Tetramers of soluble HLA-A2 molecules loaded with the antigenic peptide stained 0.4% of the patient’s blood CD8 T cells. When these cells were stimulated in clonal conditions, 25% of them proliferated, and the resulting clones were lytic and specific for the mutated malic enzyme peptide. T-cell receptor analysis indicated that almost all of these antimalic CTLs shared the same receptor. Antimalic T cells were consistently found in blood samples collected from the patient between 1990 and 1999, at frequencies ranging from 0.1 to 0.4% of the CD8 cells. Their frequency appeared to double within 2 weeks after intradermal inoculation of lethally irradiated autologous tumor cells. These results indicate that nonmelanoma cancer patients may also have a high frequency of blood CTLs directed against a tumor-specific antigen.

This article has been cited by other articles:

				F. El Hage, V. Stroobant, I. Vergnon, J.-F. Baurain, H. Echchakir, V. Lazar, S. Chouaib, P. G. Coulie, and F. Mami-Chouaib Preprocalcitonin signal peptide generates a cytotoxic T lymphocyte-defined tumor epitope processed by a proteasome-independent pathway PNAS, July 22, 2008; 105(29): 10119 - 10124. [Abstract] [Full Text] [PDF]

				G. Parmiani, A. De Filippo, L. Novellino, and C. Castelli Unique Human Tumor Antigens: Immunobiology and Use in Clinical Trials J. Immunol., February 15, 2007; 178(4): 1975 - 1979. [Abstract] [Full Text] [PDF]

				M. Sensi and A. Anichini Unique Tumor Antigens: Evidence for Immune Control of Genome Integrity and Immunogenic Targets for T Cell-Mediated Patient-Specific Immunotherapy Clin. Cancer Res., September 1, 2006; 12(17): 5023 - 5032. [Abstract] [Full Text] [PDF]

				B. Kubuschok, F. Neumann, R. Breit, M. Sester, C. Schormann, C. Wagner, U. Sester, F. Hartmann, M. Wagner, K. Remberger, et al. Naturally Occurring T-Cell Response against Mutated p21 Ras Oncoprotein in Pancreatic Cancer Clin. Cancer Res., February 15, 2006; 12(4): 1365 - 1372. [Abstract] [Full Text] [PDF]

				V. Lennerz, M. Fatho, C. Gentilini, R. A. Frye, A. Lifke, D. Ferel, C. Wolfel, C. Huber, and T. Wolfel The response of autologous T cells to a human melanoma is dominated by mutated neoantigens PNAS, November 1, 2005; 102(44): 16013 - 16018. [Abstract] [Full Text] [PDF]

				T. So, M. Takenoyama, M. Mizukami, Y. Ichiki, M. Sugaya, T. Hanagiri, K. Sugio, and K. Yasumoto Haplotype Loss of HLA Class I Antigen as an Escape Mechanism from Immune Attack in Lung Cancer Cancer Res., July 1, 2005; 65(13): 5945 - 5952. [Abstract] [Full Text] [PDF]

				M. Sensi, G. Nicolini, M. Zanon, C. Colombo, A. Molla, I. Bersani, R. Lupetti, G. Parmiani, and A. Anichini Immunogenicity without Immunoselection: A Mutant but Functional Antioxidant Enzyme Retained in a Human Metastatic Melanoma and Targeted by CD8+ T Cells with a Memory Phenotype Cancer Res., January 15, 2005; 65(2): 632 - 640. [Abstract] [Full Text] [PDF]

				G. Parmiani, A. Testori, M. Maio, C. Castelli, L. Rivoltini, L. Pilla, F. Belli, V. Mazzaferro, J. Coppa, R. Patuzzo, et al. Heat Shock Proteins and Their Use as Anticancer Vaccines Clin. Cancer Res., December 15, 2004; 10(24): 8142 - 8146. [Full Text] [PDF]

				D. Nagorsen, C. Scheibenbogen, F. M. Marincola, A. Letsch, and U. Keilholz Natural T Cell Immunity against Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4296 - 4303. [Abstract] [Full Text] [PDF]

				M. Willhauck, C. Scheibenbogen, M. Pawlita, T. Mohler, E. Thiel, and U. Keilholz Restricted T-Cell Receptor Repertoire in Melanoma Metastases Regressing after Cytokine Therapy Cancer Res., July 1, 2003; 63(13): 3483 - 3485. [Abstract] [Full Text] [PDF]

				L. Novellino, N. Renkvist, F. Rini, A. Mazzocchi, L. Rivoltini, A. Greco, P. Deho, P. Squarcina, P. F. Robbins, G. Parmiani, et al. Identification of a Mutated Receptor-Like Protein Tyrosine Phosphatase {kappa} as a Novel, Class II HLA-Restricted Melanoma Antigen J. Immunol., June 15, 2003; 170(12): 6363 - 6370. [Abstract] [Full Text] [PDF]

				W. A. E. Marijt, M. H. M. Heemskerk, F. M. Kloosterboer, E. Goulmy, M. G. D. Kester, M. A. W. G. van der Hoorn, S. A. P. van Luxemburg-Heys, M. Hoogeboom, T. Mutis, J. W. Drijfhout, et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia PNAS, March 4, 2003; 100(5): 2742 - 2747. [Abstract] [Full Text] [PDF]

				R. Salgia, T. Lynch, A. Skarin, J. Lucca, C. Lynch, K. Jung, F. S. Hodi, M. Jaklitsch, S. Mentzer, S. Swanson, et al. Vaccination With Irradiated Autologous Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Augments Antitumor Immunity in Some Patients With Metastatic Non-Small-Cell Lung Carcinoma J. Clin. Oncol., February 15, 2003; 21(4): 624 - 630. [Abstract] [Full Text] [PDF]

				H. Echchakir, G. Dorothee, I. Vergnon, J. Menez, S. Chouaib, and F. Mami-Chouaib Cytotoxic T lymphocytes directed against a tumor-specific mutated antigen display similar HLA tetramer binding but distinct functional avidity and tissue distribution PNAS, July 9, 2002; 99(14): 9358 - 9363. [Abstract] [Full Text] [PDF]

				G. Parmiani, C. Castelli, P. Dalerba, R. Mortarini, L. Rivoltini, F. M. Marincola, and A. Anichini Cancer Immunotherapy With Peptide-Based Vaccines: What Have We Achieved? Where Are We Going? J Natl Cancer Inst, June 5, 2002; 94(11): 805 - 818. [Abstract] [Full Text] [PDF]

				D. Valmori, C. Scheibenbogen, V. Dutoit, D. Nagorsen, A. M. Asemissen, V. Rubio-Godoy, D. Rimoldi, P. Guillaume, P. Romero, D. Schadendorf, et al. Circulating Tumor-reactive CD8+ T Cells in Melanoma Patients Contain a CD45RA+CCR7- Effector Subset Exerting ex Vivo Tumor-specific Cytolytic Activity Cancer Res., March 1, 2002; 62(6): 1743 - 1750. [Abstract] [Full Text] [PDF]

				P. G. Coulie, V. Karanikas, D. Colau, C. Lurquin, C. Landry, M. Marchand, T. Dorval, V. Brichard, and T. Boon A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3 PNAS, August 28, 2001; 98(18): 10290 - 10295. [Abstract] [Full Text] [PDF]