Top

Published in:

01-11-2006 | Original Article

Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells

Authors: Cheryl L.-L. Chiang, Jonathan A. Ledermann, Ariel N. Rad, David R. Katz, Benjamin M. Chain

Published in: Cancer Immunology, Immunotherapy | Issue 11/2006

Abstract

Background: Ovarian cancer commonly relapses after remission and new strategies to target microscopic residual diseases are required. One approach is to activate tumor-specific cytotoxic T cells with dendritic cells loaded with tumor cells. In order to enhance their immunogenicity, ovarian tumor cells (SK-OV-3, which express two well-characterized antigens HER-2/neu and MUC-1) were killed by oxidation with hypochlorous acid (HOCl). Results: Treatment for 1 h with 60 μM HOCl was found to induce necrosis in all SK-OV-3 cells. Oxidized, but not live, SK-OV-3 was rapidly taken up by monocyte-derived dendritic cells, and induced partial dendritic cell maturation. Dendritic cells cultured from HLA-A2 healthy volunteers were loaded with oxidized SK-OV-3 (HLA-A2⁻) and co-cultured with autologous T cells. Responding T cells were tested for specificity after a further round of antigen stimulation. In ELISPOT assays, T cells produced interferon-gamma (IFN-γ) in response to the immunizing cellular antigen, and also to peptides coding for MUC-1 and HER-2/neu HLA-A2 restricted epitopes, demonstrating efficient cross-presentation of cell-associated antigens. In contrast, no responses were seen after priming with heat-killed or HCl-killed SK-OV-3, indicating that HOCl oxidation and not cell death/necrosis per se enhanced the immunogenicity of SK-OV-3. Finally, T cells stimulated with oxidized SK-OV-3 showed no cross-reaction to oxidized melanoma cells, nor vice versa, demonstrating that the response was tumor-type specific. Conclusions: Immunization with oxidized ovarian tumor cell lines may represent an improved therapeutic strategy to stimulate a polyclonal anti-tumor cellular immune response and hence extend remission in ovarian cancer.

Allison ME, Fearon DT (2000) Enhanced immunogenicity of aldehyde-bearing antigens: a possible link between innate and adaptive immunity. Eur J Immunol 30:2881–2887PubMedCrossRef

Barratt-Boyes SM, Vlad A, Finn OJ (1999) Immunization of chimpanzees with tumor antigen MUC1 mucin tandem repeat peptide elicits both helper and cytotoxic T-cell responses. Clin Cancer Res 5:1918–1924PubMed

Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539–1546PubMedCrossRef

Brossart P, Heinrich KS, Stuhler G, Behnke L, Reichardt VL, Stevanovic S, Muhm A, Rammensee HG, Kanz L, Brugger W (1999) Identification of HLA-A2-restricted T-cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. Blood 93:4309–4317PubMed

Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W (2000) Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 96:3102–3108PubMed

Cerundolo V, Hermans IF, Salio M (2004) Dendritic cells: a journey from laboratory to clinic. Nat Immunol 5:7–10PubMedCrossRef

Chen Z, Moyana T, Saxena A, Warrington R, Jia Z, Xiang J (2001) Efficient antitumor immunity derived from maturation of dendritic cells that had phagocytosed apoptotic/necrotic tumor cells. Int J Cancer 93:539–548PubMedCrossRef

Disis ML, Schiffman K (2001) Cancer vaccines targeting the HER2/neu oncogenic protein. Semin Oncol 28:12–20PubMedCrossRef

Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K (2002) Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 20:2624–2632PubMedCrossRef

10.

Fisk B, Blevins TL, Wharton JT, Ioannides CG (1995) Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med 181:2109–2117PubMedCrossRef

11.

Gritzapis AD, Sotiriadou NN, Papamichail M, Baxevanis CN (2004) Generation of human tumor-specific CTLs in HLA-A2.1-transgenic mice using unfractionated peptides from eluates of human primary breast and ovarian tumors. Cancer Immunol Immunother 53:1027–1040PubMedCrossRef

12.

Hernando JJ, Park TW, Kubler K, Offergeld R, Schlebusch H, Bauknecht T (2002) Vaccination with autologous tumour antigen-pulsed dendritic cells in advanced gynaecological malignancies: clinical and immunological evaluation of a phase I trial. Cancer Immunol Immunother 51:45–52PubMedCrossRef

13.

Holmberg LA, Sandmaier B (2004) Vaccination as a treatment for breast or ovarian cancer. Expert Rev Vaccines 3:269–277PubMedCrossRef

14.

Hwu P, Freedman RS (2002) The immunotherapy of patients with ovarian cancer. J Immunother 25:189–201PubMedCrossRef

15.

Kotera Y, Shimizu K, Mule JJ (2001) Comparative analysis of necrotic and apoptotic tumor cells as a source of antigen(s) in dendritic cell-based immunization. Cancer Res 61:8105–8109PubMed

16.

Marcinkiewicz J (1997) Neutrophil chloramines: missing links between innate and acquired immunity. Immunol Today 18:577–580PubMedCrossRef

17.

Marcinkiewicz J, Chain BM, Olszowska E, Olszowski S, Zgliczynski JM (1991) Enhancement of immunogenic properties of ovalbumin as a result of its chlorination. Int J Biochem 23:1393–1395PubMedCrossRef

18.

Marcinkiewicz J, Olszowska E, Olszowski S, Zgliczynski JM (1992) Enhancement of trinitrophenyl-specific humoral response to TNP proteins as the result of carrier chlorination. Immunology 76:385–388PubMed

19.

Morisaki T, Matsumoto K, Onishi H, Kuroki H, Baba E, Tasaki A, Kubo M, Nakamura M, Inaba S, Yamaguchi K, Tanaka M, Katano M (2003) Dendritic cell-based combined immunotherapy with autologous tumor-pulsed dendritic cell vaccine and activated T cells for cancer patients: rationale, current progress, and perspectives. Hum Cell 16:175–182PubMedCrossRef

20.

Murray JL, Gillogly ME, Przepiorka D, Brewer H, Ibrahim NK, Booser DJ, Hortobagyi GN, Kudelka AP, Grabstein KH, Cheever MA, Ioannides CG (2002) Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369–377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer. Clin Cancer Res 8:3407–3418PubMed

21.

Palmer K, Moore J, Everard M, Harris JD, Rodgers S, Rees RC, Murray AK, Mascari R, Kirkwood J, Riches PG, Fisher C, Thomas JM, Harries M, Johnston SR, Collins MK, Gore ME (1999) Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma. Hum Gene Ther 10:1261–1268PubMedCrossRef

22.

Palucka AK, Dhodapkar MV, Paczesny S, Burkeholder S, Wittkowski KM, Steinman RM, Fay J, Banchereau J (2003) Single injection of CD34+ progenitor-derived dendritic cell vaccine can lead to induction of T-cell immunity in patients with stage IV melanoma. J Immunother 26:432–439PubMedCrossRef

23.

Peoples GE, Goedegebuure PS, Smith R, Linehan DC, Yoshino I, Eberlein TJ (1995) Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA 92:432–436PubMedCrossRef

24.

Rad AN, Pollara G, Sohaib SM, Chiang C, Chain BM, Katz DR (2003) The differential influence of allogeneic tumor cell death via DNA damage on dendritic cell maturation and antigen presentation. Cancer Res 63:5143–5150PubMed

25.

Renard V, Sonderbye L, Ebbehoj K, Rasmussen PB, Gregorius K, Gottschalk T, Mouritsen S, Gautam A, Leach DR (2003) HER-2 DNA and protein vaccines containing potent Th cell epitopes induce distinct protective and therapeutic antitumor responses in HER-2 transgenic mice. J Immunol 171:1588–1595PubMed

26.

Santin AD, Bellone S, Palmieri M, Bossini B, Cane S, Bignotti E, Roman JJ, Cannon MJ, Pecorelli S (2004) Restoration of tumor specific human leukocyte antigens class I-restricted cytotoxicity by dendritic cell stimulation of tumor infiltrating lymphocytes in patients with advanced ovarian cancer. Int J Gynecol Cancer 14:64–75PubMedCrossRef

27.

Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N (2000) Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells [see comments]. J Exp Med 191:423–434PubMedCrossRef

28.

Schuler G, Schuler-Thurner B, Steinman RM (2003) The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 15:138–147PubMedCrossRef

29.

Shaif-Muthana M, McIntyre C, Sisley K, Rennie I, Murray A (2000) Dead or alive: immunogenicity of human melanoma cells when presented by dendritic cells. Cancer Res 60:6441–6447PubMed

30.

Slingluff CL Jr, Petroni GR, Yamshchikov GV, Barnd DL, Eastham S, Galavotti H, Patterson JW, Deacon DH, Hibbitts S, Teates D, Neese PY, Grosh WW, Chianese-Bullock KA, Woodson EM, Wiernasz CJ, Merrill P, Gibson J, Ross M, Engelhard VH (2003) Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol 21:4016–4026PubMedCrossRef

31.

Wolpoe ME, Lutz ER, Ercolini AM, Murata S, Ivie SE, Garrett ES, Emens LA, Jaffee EM, Reilly RT (2003) HER-2/neu-specific monoclonal antibodies collaborate with HER-2/neu-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8+ T cell effector function and tumor-free survival in Her-2/neu-transgenic mice. J Immunol 171:2161–2169PubMed

32.

Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213PubMedCrossRef

Title: Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells
Authors: Cheryl L.-L. Chiang
Jonathan A. Ledermann
Ariel N. Rad
David R. Katz
Benjamin M. Chain
Publication date: 01-11-2006
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 11/2006
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0127-9

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 11/2006

Enhancement of anti-tumor immunity specific to murine glioma by vaccination with tumor cell lysate-pulsed dendritic cells engineered to produce interleukin-12

Antitumor action and immune activation through cooperation of bee venom secretory phospholipase A2 and phosphatidylinositol-(3,4)-bisphosphate

PankoMab: a potent new generation anti-tumour MUC1 antibody

Autologous control of a highly malignant syngeneic CRNK-16 leukemia in the rat: a role for NK cells

International Society for Cell and Gene Therapy of Cancer (ISCGT) annual meeting: conference overview and introduction to the symposium papers

Immune enhancement and anti-tumour activity of IL-23

Keynote webinar | Spotlight on antibody–drug conjugates in cancer