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Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
A majority of the human tumor-associated Ags characterized to date are derived from nonmutated "self"-proteins. Little is currently understood about the nature of the self-reactive lymphocytes that recognize these Ags. We recently characterized two nonmutated tumor-associated Ags for the B16 murine melanoma: tyrosinase-related protein-2 (TRP-2) and the endogenous retroviral envelope protein, p15E. We previously reported that both TRP-2 and p15E reactive CTL could be detected in the spleens of naive animals after a single in vitro stimulation using 10-5–10-6 M of the appropriate Kb-binding 9-amino acid epitope. In this report we show that the CTL found in naive animals are low avidity lymphocytes, that respond only to high concentrations of peptide in vitro. We demonstrate that titration of in vitro-stimulating peptide to limiting concentrations distinguishes qualitative differences in the lymphocyte reactivity to these two Ags between vaccinated and unvaccinated animals. We further demonstrate that in vitro expansion of CTL in either high or low concentrations of stimulating peptide generated CTL cultures with different avidities for the relevant epitopes. CTL expanded in low concentrations demonstrated higher avidity for peptide-pulsed targets and better tumor recognition, when compared to CTL generated in the presence of high concentrations of Ag. More importantly, high avidity CTL demonstrated superior in vivo antitumor activity. These results demonstrate that qualitative differences in the CTL that recognize these two self-Ags are critically important to their in vitro and in vivo anti-tumor efficacy.
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T. N. J. Bullock, D. W. Mullins, T. A. Colella, and V. H. Engelhard Manipulation of Avidity to Improve Effectiveness of Adoptively Transferred CD8+ T Cells for Melanoma Immunotherapy in Human MHC Class I-Transgenic Mice J. Immunol., November 15, 2001; 167(10): 5824 - 5831. [Abstract] [Full Text] [PDF]
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V. Dutoit, V. Rubio-Godoy, P.-Y. Dietrich, A.-L. Quiqueres, V. Schnuriger, D. Rimoldi, D. Lienard, D. Speiser, P. Guillaume, P. Batard, et al. Heterogeneous T-Cell Response to MAGE-A10254-262: High Avidity-specific Cytolytic T Lymphocytes Show Superior Antitumor Activity Cancer Res., August 1, 2001; 61(15): 5850 - 5856. [Abstract] [Full Text] [PDF]
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R. W. Tindle, K. Herd, T. Doan, G. Bryson, G. R. Leggatt, P. Lambert, I. H. Frazer, and M. Street Nonspecific Down-Regulation of CD8+ T-Cell Responses in Mice Expressing Human Papillomavirus Type 16 E7 Oncoprotein from the Keratin-14 Promoter J. Virol., July 1, 2001; 75(13): 5985 - 5997. [Abstract] [Full Text] [PDF]
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S. K. Mendiratta, G. Thai, N. K. Eslahi, N. M. Thull, M. Matar, V. Bronte, and F. Pericle Therapeutic Tumor Immunity Induced by Polyimmunization with Melanoma Antigens gp100 and TRP-2 Cancer Res., February 1, 2001; 61(3): 859 - 863. [Abstract] [Full Text]
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M. Harada, Y. F. Li, M. El-Gamil, S. A. Rosenberg, and P. F. Robbins Use of an in Vitro Immunoselected Tumor Line to Identify Shared Melanoma Antigens Recognized by HLA-A*0201-restricted T Cells Cancer Res., February 1, 2001; 61(3): 1089 - 1094. [Abstract] [Full Text]
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M. A. Derby, M. A. Alexander-Miller, R. Tse, and J. A. Berzofsky High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL J. Immunol., February 1, 2001; 166(3): 1690 - 1697. [Abstract] [Full Text] [PDF]
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M. W. J. Schreurs, A. A. O. Eggert, A. J. de Boer, J. L. M. Vissers, T. van Hall, R. Offringa, C. G. Figdor, and G. J. Adema Dendritic Cells Break Tolerance and Induce Protective Immunity against a Melanocyte Differentiation Antigen in an Autologous Melanoma Model Cancer Res., December 1, 2000; 60(24): 6995 - 7001. [Abstract] [Full Text]
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H. Yamada, G. Matsuzaki, Y. Iwamoto, and K. Nomoto Unusual cytotoxic activities of thymus-independent, self-antigen-specific CD8+ T cells Int. Immunol., December 1, 2000; 12(12): 1677 - 1683. [Abstract] [Full Text] [PDF]
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M. Bellone, D. Cantarella, P. Castiglioni, M. C. Crosti, A. Ronchetti, M. Moro, M. P. Garancini, G. Casorati, and P. Dellabona Relevance of the Tumor Antigen in the Validation of Three Vaccination Strategies for Melanoma J. Immunol., September 1, 2000; 165(5): 2651 - 2656. [Abstract] [Full Text] [PDF]
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N. Kienzle, M. Buck, S. L. Silins, S. R. Burrows, D. J. Moss, A. Winterhalter, A. Brooks, and R. Khanna Differential Splicing of Antigen-Encoding RNA Reduces Endogenous Epitope Presentation That Regulates the Expansion and Cytotoxicity of T Cells J. Immunol., August 15, 2000; 165(4): 1840 - 1846. [Abstract] [Full Text] [PDF]
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L. Jenne, J.-F. Arrighi, H. Jonuleit, J.-H. Saurat, and C. Hauser Dendritic Cells Containing Apoptotic Melanoma Cells Prime Human CD8+ T Cells for Efficient Tumor Cell Lysis Cancer Res., August 1, 2000; 60(16): 4446 - 4452. [Abstract] [Full Text]
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 S. M. Dubinett, R. K. Batra, P. W. Miller, and S. Sharma Tumor Antigens in Thoracic Malignancy Am. J. Respir. Cell Mol. Biol., May 1, 2000; 22(5): 524 - 527. [Full Text]
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