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Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer

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Abstract

We are investigating the use of Alpha Fetoprotein (AFP) as a tumor rejection antigen for hepatocellular carcinoma (HCC). We recently completed vaccination of 10 AFP+/HLA-A2.1+ HCC subjects with AFP peptide-pulsed autologous dendritic cells (DC). There were increased frequencies of circulating AFP-specific T cells and of IFNγ-producing AFP-specific T cells after vaccination. In order to better understand the lack of association between immune response and clinical response, we have examined additional aspects of the AFP immune response in patients. Here, we have characterized the cell surface phenotype of circulating AFP tetramer-positive CD8 T cells and assessed AFP-specific CD4 function. Before vaccination, HCC subjects had increased frequencies of circulating AFP-specific CD8 T cells with a range of naïve, effector, central and effector memory phenotypes. Several patients had up-regulated activation markers. A subset of patients was assessed for phenotypic changes pre- and post-vaccination, and evidence for complete differentiation to effector or memory phenotype was lacking. CD8 phenotypic and cytokine responses did not correlate with level of patient serum AFP antigen (between 74 and 463,040 ng/ml). Assessment of CD4+ T cell responses by ELISPOT and multi-cytokine assay did not identify any spontaneous CD4 T cell responses to this secreted protein. These data indicate that there is an expanded pool of partially differentiated AFP-specific CD8 T cells in many of these HCC subjects, but that these cells are largely non-functional, and that a detectable CD4 T cell response to this secreted oncofetal antigen is lacking.

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Abbreviations

AFP:

Alpha fetoprotein

AFP+:

AFP-expressing

HCC:

Hepatocellular cancer

DC:

Dendritic cell(s)

PBMC:

Peripheral blood mononuclear cells

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Acknowledgments

This work was supported by NIH/NCI ROI CA 77623, RO1 CA 79976 (JSE), and by a Scientist Development Grant from the American Heart Association (#0330102N), the University of Pittsburgh Cancer Institute, the Pittsburgh Foundation and the Henry L. Hillman Foundation (LHB). We wish to acknowledge the expertise of the UPCI Flow Cytometry Facility and Erin McClelland and especially Drs. Albert D. and Vera S. Donnenberg for several helpful discussions. Also our thanks to the UPCI Luminex Facility, Dr. Anna Lokshin, Director.

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Correspondence to Lisa H. Butterfield.

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Butterfield, L.H., Ribas, A., Potter, D.M. et al. Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer. Cancer Immunol Immunother 56, 1931–1943 (2007). https://doi.org/10.1007/s00262-007-0337-9

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  • DOI: https://doi.org/10.1007/s00262-007-0337-9

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