Advertisement

Generation of CA125-specific cytotoxic T lymphocytes in human leukocyte antigen-A2.1-positive healthy donors and patients with advanced ovarian cancer

Published:November 03, 2008DOI:https://doi.org/10.1016/j.ajog.2008.08.014

      Objective

      To identify potential immunogenic peptides derived from CA125.

      Study Design

      A bioinformatics approach was used to identify peptides derived from CA125 that bind to human leukocyte antigen A2.1 and elicit peptide-specific human cytotoxic T-lymphocyte responses in healthy individuals and patients with ovarian carcinoma.

      Results

      CD8+ cytotoxic T-lymphocyte populations generated against 4 CA125-derived peptides were able to induce lysis of autologous peptide-loaded target cells. CA125 YTLDrDSLYV peptide-specific cytotoxic T lymphocytes were found to effectively kill ovarian tumors expressing CA125. Cytotoxicity was inhibited by antihuman leukocyte antigen A2.1 (BB7-2) and antihuman leukocyte antigen class I (W6/32) antibodies, whereas natural killer-sensitive targets were not lysed. YTLDrDSLYV peptide-specific cytotoxic T lymphocyte precursor frequency was low in peripheral blood leukocytes of normal donors and patients with ovarian cancer as determined by interferon-gamma production in ELISPOT assays. Intracellular cytokine expression measured by flow cytometry showed a type 1 cytokine profile in YTLDrDSLYV peptide-specific cytotoxic T lymphocytes.

      Conclusion

      The CA125 YTLDrDSLYV peptide is an immunogenic epitope and may represent an attractive target for immunotherapy of ovarian cancer.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jemal A.
        • Siegel R.
        • Ward E.
        • Murray T.
        • Xu J.
        • Thun M.J.
        Cancer statistics, 2007.
        CA Cancer J Clin. 2007; 57: 43-66
        • DiSaia P.J.
        • Creasman W.T.
        Clinical gynecologic oncology: invasive cervical cancer.
        in: 5th ed. Mosby-Year Book, St Louis1997: 51-106
        • Bast Jr, R.C.
        • Feeney M.
        • Lazarus H.
        • Nadler L.M.
        • Colvin R.B.
        • Knapp R.C.
        Reactivity of a monoclonal antibody with human ovarian carcinoma.
        J Clin Invest. 1981; 68: 1331-1337
        • Bast Jr, R.C.
        • Badgwell D.
        • Lu Z.
        • et al.
        New tumor markers: CA125 and beyond.
        Int J Gynecol Cancer. 2005; 15: 274-281
        • Rustin G.J.
        • Nelstrop A.E.
        • McClean P.
        • et al.
        Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125.
        J Clin Oncol. 1996; 14: 1545-1551
        • Wagner U.
        • Kohler S.
        • Reinartz S.
        • et al.
        Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment.
        Clin Cancer Res. 2001; 7: 1154-1162
        • Reinartz S.
        • Kohler S.
        • Schlebusch H.
        • et al.
        Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II).
        Clin Cancer Res. 2004; 10: 1580-1587
        • Berek J.S.
        • Taylor P.T.
        • Gordon A.
        • et al.
        Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer.
        J Clin Oncol. 2004; 22: 3507-3516
        • Gordon A.N.
        • Schultes B.C.
        • Gallion H.
        • et al.
        CA125- and tumor-specific T-cell responses correlate with prolonged survival in oregovomab-treated recurrent ovarian cancer patients.
        Gynecol Oncol. 2004; 94: 340-351
        • Ehlen T.G.
        • Hoskins P.J.
        • Miller D.
        • et al.
        A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer.
        Int J Gynecol Cancer. 2005; 15: 1023-1034
        • O'Brien T.J.
        • Beard J.B.
        • Underwood L.J.
        • Dennis R.A.
        • Santin A.D.
        • York L.
        The CA 125 gene: an extracellular superstructure dominated by repeat sequences.
        Tumour Biol. 2001; 22: 348-366
        • O'Brien T.J.
        • Beard J.B.
        • Underwood L.J.
        • Shigemasa K.
        The CA 125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure.
        Tumour Biol. 2002; 23: 154-169
        • Yin B.W.
        • Lloyd K.O.
        Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16.
        J Biol Chem. 2001; 276: 27371-27375
        • Zeh 3rd, H.J.
        • Leder G.H.
        • Lotze M.T.
        • et al.
        Flow-cytometric determination of peptide-class I complex formation: identification of p53 peptides that bind to HLA-A2.
        Human Immunol. 1994; 39: 79-86
        • Santin A.D.
        • Bellone S.
        • Ravaggi A.
        • Pecorelli S.
        • Cannon M.J.
        • Parham G.P.
        Induction of ovarian tumor-specific CD8+ cytotoxic T lymphocytes by acid-eluted peptide-pulsed autologous dendritic cells.
        Obstet Gynecol. 2000; 96: 422-430
        • Santin A.D.
        • Hermonat P.L.
        • Ravaggi A.
        • et al.
        Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells.
        Clin Cancer Res. 2001; 7: 804s-810s
        • Holloway R.W.
        • Mehta R.S.
        • Finkler N.J.
        • et al.
        Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients.
        Gynecol Oncol. 2002; 87: 8-16
        • Santin A.D.
        • Zhan F.
        • Bellone S.
        • et al.
        Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy.
        Int J Cancer. 2004; 112: 14-25
        • Bignotti E.
        • Tassi R.A.
        • Calza S.
        • et al.
        Differential gene expression profiles between tumor biopsies and short-term primary cultures of ovarian serous carcinomas: identification of novel molecular biomarkers for early diagnosis and therapy.
        Gynecol Oncol. 2006; 103: 405-416
        • Tsang K.Y.
        • Palena C.
        • Gulley J.
        • Arlen P.
        • Schlom J.
        A human cytotoxic T-lymphocyte epitope and its agonist epitope from the nonvariable number of tandem repeat sequence of MUC-1.
        Clin Cancer Res. 2004; 10: 2139-2149
        • Wierecky J.
        • Mueller M.
        • Brossart P.
        Dendritic cell-based cancer immunotherapy targeting MUC-1.
        Cancer Immunol Immunother. 2006; 55: 63-67
        • Schuler G.
        • Steinman R.M.
        Dendritic cells as adjuvants for immune-mediated resistance to tumors.
        J Exp Med. 1997; 186: 1183-1187
        • Banchereau J.
        • Steinman R.M.
        Dendritic cells and the control of immunity.
        Nature. 1998; 392: 245-252
        • Osada T.
        • Clay T.M.
        • Woo C.Y.
        • Morse M.A.
        • Lyerly H.K.
        Dendritic cell-based immunotherapy.
        Int Rev Immunol. 2006; 25: 377-413
        • Schultes B.C.
        • Whiteside T.L.
        Monitoring of immune responses to CA125 with an IFN-gamma ELISPOT assay.
        J Immunol Methods. 2003; 279: 1-15
        • Ge Q.
        • Rao V.P.
        • Cho B.K.
        • Eisen H.N.
        • Chen J.
        Dependence of lymphopenia-induced T cell proliferation on the abundance of peptide/MHC epitopes and strength of their interaction with T cell receptors.
        Proc Natl Acad Sci U S A. 2001; 98: 1728-1733
        • Valitutti S.
        • Muller S.
        • Dessing M.
        • Lanzavecchia A.
        Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy.
        J Exp Med. 1996; 183: 1917-1921
        • Zhang L.
        • Conejo-Garcia J.R.
        • Katsaros D.
        • et al.
        Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
        N Engl J Med. 2003; 348: 203-213