Abstract
The various immunological roles of human alpha-fetoprotein (HAFP), and its correlation with hepatomas, that is, hepatocellular carcinomas (HCCs), are not often addressed together in biomedical reports considering that HAFP is an established biomarker for hepatomas. Studies reporting measurement of HAFP serum levels in hepatoma patients in basic/clinical research settings has greatly increased over the years. Recent reports have now expanded our base knowledge in the mounting of an immune response against AFP, a self antigen, during hepatoma tumorigenesis. Advances in the detection and identification of AFP-derived peptide epitopes are opening new vistas of knowledge regarding the immunological role of AFP-peptides as T cell stimulating antigens in the course of hepatoma growth and progression. The present commentary addresses HAFP-derived peptides as immunologic responders in HCC and their use in the study and generation of AFP-peptide sensitized T cells directed against hepatoma cells. Attempts were further made to relate the AFP-derived peptide epitopes to T cell activities during the course of hepatoma immunotherapies and to profile the traits and properties of the peptides themselves. Hence, the present commentary was divided into two sections; (1) the characterization, properties, and traits of AFP peptide epitopes, and (2) the use of AFP-derived peptides in the therapeutic induction of T cells primed against hepatoma cells using both in vivo and in vitro models.
Abbreviations
- APC:
-
Antigen presenting cells
- CTL:
-
Cytotoxic T-Lymphocyte
- DC:
-
Dendritic cells
- HAFP:
-
Human alpha-fetoprotein
- HCC:
-
Hepatocellular carcinoma
- HLA:
-
Human lymphocyte antigen
- IFNgamma:
-
Interferon gamma
- IL:
-
Interleukin (IL-2, IL-13, etc.)
- LPS:
-
Lipopolysaccharide TCR, T cell receptor
- MHC:
-
Major histocompability complex
- POLY I: C:
-
Polyinosinic:polycytidylic acid
- TCGF:
-
T cell growth factor
- TNF:
-
Tumor necrosis factor
References
Abelev GI, Eraiser TL (1999) Cellular aspects of alpha-fetoprotein reexpression in tumors. Semin Cancer Biol 9:95–107
Alisa A, Boswell S, Pathan AA, Ayaru L, Williams R, Behboudi S (2008) Human CD4 + T cells recognize an epitope within alpha-fetoprotein sequence and develop into TGF-{beta}-producing CD4 + T Cells. J Immunol 180:5109–5117
Altman DJ, Schneider SL, Thompson DA, Cheng HL, Tomasi TB (1990) A transforming growth factor beta 2 (TGF-beta 2)-like immunosuppressive factor in amniotic fluid and localization of TGF-beta 2 mRNA in the pregnant uterus. J Exp Med 172:1391–1401
Ayaru L, Pereira SP, Alisa A, Pathan AA, Williams R, Davidson B, Burroughs AK, Meyer T, Behboudi S (2007) Unmasking of alpha-fetoprotein-specific CD4(+) T cell responses in hepatocellular carcinoma patients undergoing embolization. J Immunol 178:1914–1922
Bui LA, Butterfield LH, Kim JY, Ribas A, Seu P, Lau R, Glaspy JA, McBride WH, Economou JS (1997) In vivo therapy of hepatocellular carcinoma with a tumor-specific adenoviral vector expressing interleukin–2. Hum Gene Ther 8:2173–2182
Butterfield LH, Koh A, Meng W, Vollmer CM, Ribas A, Dissette V, Lee E, Glaspy JA, McBride WH, Economou JS (1999) Generation of human T cell responses to an HLA-A2.1-restricted peptide epitope derived from alpha-fetoprotein. Cancer Res 59:3134–3142
Butterfield LH, Meng WS, Koh A, Vollmer CM, Ribas A, Dissette VB, Faull K, Glaspy JA, McBride WH, Economou JS (2001) T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein. J Immunol 166:5300–5308
Butterfield LH, Ribas A, Dissette VB, Lee Y, Yang JQ, De la Rocha P, Duran SD, Hernandez J, Seja E, Potter DM, McBride WH, Finn R, Glaspy JA, Economou JS (2006) A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 12:2817–2825
Butterfield LH, Ribas A, Meng WS, Dissette VB, Amarnani S, Vu HT, Seja E, Todd K, Glaspy JA, McBride WH, Economou JS (2003) T cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res 9:5902–5908
Butterfield LH, Ribas A, Potter DM, Economou JS (2007) Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer. Cancer Immunol Immunother 56:1931–1943
Chen H, Egan JO, Chiu JF (1997) Regulation and activities of alpha-fetoprotein. Crit Rev Eukaryot Gene Expr 7:11–41
De Mees C, Laes JF, Bakker J, Smitz J, Hennuy B, Van Vooren P, Gabant P, Szpirer J, Szpirer C (2006) Alpha-fetoprotein controls female fertility and prenatal development of the gonadotropin-releasing hormone pathway through an antiestrogenic action. Mol Cell Biol 26:2012–2018
Dudich E (2007) MM-093, a recombinant human alpha-fetoprotein for the potential treatment of rheumatoid arthritis and other autoimmune diseases. Curr Opin Mol Ther 9:603–610
Gabant P, Forrester L, Nichols J, Van Reeth T, De Mees C, Pajack B, Watt A, Smitz J, Alexandre H, Szpirer C, Szpirer J (2002) Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility. Proc Natl Acad Sci USA 99:12865–12870
Garcia KC, Degano M, Pease LR, Huang M, Peterson PA, Teyton L, Wilson IA (1998) Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279:1166–1172
Geissler M, Mohr L, Weth R, Kohler G, Grimm CF, Krohne TU, von Weizsacker F, Blum HE (2001) Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice. Gastroenterology 121:931–939
Gillespie JR, Uversky VN (2000) Structure and function of alpha-fetoprotein: a biophysical overview. Biochim Biophys Acta 1480:41–56
Gonzalez-Carmona MA, Marten A, Hoffmann P, Schneider C, Sievers E, Schmidt-Wolf IG, Sauerbruch T, Caselmann WH (2006) Patient-derived dendritic cells transduced with an a-fetoprotein-encoding adenovirus and co-cultured with autologous cytokine-induced lymphocytes induce a specific and strong immune response against hepatocellular carcinoma cells. Liver Int 26:369–379
Hanke P, Rabe C, Serwe M, Bohm S, Pagenstecher C, Sauerbruch T, Caselmann WH (2002) Cirrhotic patients with or without hepatocellular carcinoma harbour AFP-specific T-lymphocytes that can be activated in vitro by human alpha-fetoprotein. Scand J Gastroenterol 37:949–955
Isaacs H Jr (2007) Fetal and neonatal hepatic tumors. J Pediatr Surg 42:1797–1803
Johnson PJ, Poon TC, Hjelm NM, Ho CS, Blake C, Ho SK (2000) Structures of disease-specific serum alpha-fetoprotein isoforms. Br J Cancer 83:1330–1337
Lazarevich NL (2000) Molecular mechanisms of alpha-fetoprotein gene expression. Biochemistry (Mosc) 65:117–133
Liu Y, Daley S, Evdokimova VN, Zdobinski DD, Potter DM, Butterfield LH (2006) Hierarchy of alpha fetoprotein (AFP)-specific T cell responses in subjects with AFP-positive hepatocellular cancer. J Immunol 177:712–721
Madden DR, Garboczi DN, Wiley DC (1993) The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell 75:693–708
Meng WS, Butterfield LH, Ribas A, Dissette VB, Heller JB, Miranda GA, Glaspy JA, McBride WH, Economou JS (2001) alpha-Fetoprotein-specific tumor immunity induced by plasmid prime-adenovirus boost genetic vaccination. Cancer Res 61:8782–8786
Meng WS, Butterfield LH, Ribas A, Heller JB, Dissette VB, Glaspy JA, McBride WH, Economou JS (2000) Fine specificity analysis of an HLA-A2.1-restricted immunodominant T cell epitope derived from human alpha-fetoprotein. Mol Immunol 37:943–950
Miley MJ, Messaoudi I, Metzner BM, Wu Y, Nikolich-Zugich J, Fremont DH (2004) Structural basis for the restoration of TCR recognition of an MHC allelic variant by peptide secondary anchor substitution. J Exp Med 200:1445–1454
Mizejewski GJ (1997) alpha-fetoprotein as a biologic response modifier: relevance to domain and subdomain structure. Proc Soc Exp Biol Med 215:333–362
Mizejewski GJ (2001) Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants. Exp Biol Med (Maywood) 226:377–408
Mizejewski GJ (2002) Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy. Expert Rev Anticancer Ther 2:709–735
Mizejewski GJ (2003) Levels of alpha-fetoprotein during pregnancy and early infancy in normal and disease states. Obstet Gynecol Surv 58:804–826
Mizejewski GJ (1995) The phylogeny of alpha-fetoprotein in vertebrates: survey of biochemical and physiological data. Crit Rev Eukaryot Gene Expr 5:281–316
Mizukoshi E, Nakamoto Y, Tsuji H, Yamashita T, Kaneko S (2006) Identification of alpha-fetoprotein-derived peptides recognized by cytotoxic T lymphocytes in HLA-A24 + patients with hepatocellular carcinoma. Int J Cancer 118:1194–1204
Nahas SA, Duquette A, Roddier K, Gatti RA, Brais B (2007) Ataxia-oculomotor apraxia 2 patients show no increased sensitivity to ionizing radiation. Neuromuscul Disord 17:968–969
Sherman M (2001) Alphafetoprotein: an obituary. J Hepatol 34:603–605
Um SH, Mulhall C, Alisa A, Ives AR, Karani J, Williams R, Bertoletti A, Behboudi S (2004) Alpha-fetoprotein impairs APC function and induces their apoptosis. J Immunol 173:1772–1778
Vollmer CM Jr, Eilber FC, Butterfield LH, Ribas A, Dissette VB, Koh A, Montejo LD, Lee MC, Andrews KJ, McBride WH, Glaspy JA, Economou JS (1999) Alpha-fetoprotein-specific genetic immunotherapy for hepatocellular carcinoma. Cancer Res 59:3064–3067
Wepsic HT (1981) Alpha-fetoprotein: Its quantitation and relationship to neoplastic disease. Masson Publ, New York, NY, pp 115–129
Yano H, Basaki Y, Oie S, Ogasawara S, Momosaki S, Akiba J, Nishida N, Kojiro S, Ishizaki H, Moriya F, Kuratomi K, Fukahori S, Kuwano M, Kojiro M (2007) Effects of IFN-alpha on alpha-fetoprotein expressions in hepatocellular carcinoma cells. J Interferon Cytokine Res 27:231–238
Zhang HM, Zhang LW, Ren J, Fan L, Si XM, Liu WC (2006) Induction of alpha-fetoprotein-specific CD4- and CD8-mediated T cell response using RNA-transfected dendritic cells. Cell Immunol 239:144–150
Acknowledgments
The author extends his thanks and gratitude to Jennifer L. Wright for her commitment and time expenditure in the excellent typing and processing of the manuscript, references, and tables of the present report.
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Mizejewski, G.J. Alpha-fetoprotein (AFP)-derived peptides as epitopes for hepatoma immunotherapy: a commentary. Cancer Immunol Immunother 58, 159–170 (2009). https://doi.org/10.1007/s00262-008-0548-8
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DOI: https://doi.org/10.1007/s00262-008-0548-8