Tumor Regression and Autoimmunity after Reversal of a Functionally Tolerant State of Self-reactive CD8+ T Cells
By W. Overwijk, M. Theoret, S. Finkelstein, D. Surman, L. A. de Jong, F. Vyth-Dreese, T. Dellemijn, P. Antony, P. Spiess, D. Palmer and 8 more. Journal of Experimental Medicine, 2003
1,015 citations recorded by the source corpus.
Many tumor-associated antigens are derived from nonmutated “self” proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I–restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.
Subfields: Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/42d4ef5efe98d27a4898cea89bc2a465344ba6b0
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Citations in the corpus
- Adoptive immunotherapy for cancer: harnessing the T cell response (2012, neutral): “Bunun aynısı transfer edilmiş hücrelerle bir aşı uygulamasıyla in vivo olarakta yerine getirilebilir (158).”
- Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells (2009, methodology): “We stimulated carboxyfluorescein succinimidyl ester (CFSE)-labeled CD8 + T cells from the gp100-specific T cell receptor (TCR)-transgenic mouse, pmel-1 (ref”
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- Adoptive cell transfer: a clinical path to effective cancer immunotherapy (2008, background): “More recently, T-cell receptor (TCR) transgenic mice, all of whose lymphocytes express anti- gp100 tumour antigen TCRs, have provided a constant source of anti-tumour T cells that are valuable for defining host factors and cell properties associated with effective ACT of large, vascularized, subcut”
- Interluekin-12 enhances the function and anti-tumor activity in murine and human CD8+ T cells (2015, methodology): “1), pmel-1 TCR transgenic [25], HLA-A2 transgenic, IFNγ−/−, and NSG mice were obtained from Jackson Laboratory (Bar Harbor, ME).”
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- Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer (2010, neutral): “Mice and cell lines Pmel-1 TCR transgenic (24, 25) and C57BL/6 mice (The Jackson Laboratory) were bred, housed, and used according to the guidelines of the National Cancer Institute Animal Care and Use Committee.”
- CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells (2005, methodology): “pmel-1 TCR transgenic mice have been described previously (23).”