Top

Published in:

01-02-2007 | Original Article

Melanocyte differentiation antigen RAB38/NY-MEL-1 induces frequent antibody responses exclusively in melanoma patients

Authors: Alfred Zippelius, Asma Gati, Tammo Bartnick, Senta Walton, Bernhard Odermatt, Elke Jaeger, Reinhold Dummer, Mirjana Urosevic, Valeriy Filonenko, Kazuhiro Osanai, Holger Moch, Yao-Tseng Chen, Lloyd J. Old, Alexander Knuth, Dirk Jaeger

Published in: Cancer Immunology, Immunotherapy | Issue 2/2007

Abstract

Expression pattern and immunogenicity are critical issues that define tumor antigens as diagnostic markers and potential targets for immunotherapy. The development of SEREX (serological analysis of recombinant expression libraries) has provided substantial progress in the identification of tumor antigens eliciting both cellular and humoral immune responses in cancer patients. By SEREX, we have previously identified RAB38/NY-MEL-1 as a melanocyte differentiation antigen that is highly expressed in normal melanocytes and melanoma tissues but not in other normal tissues or cancer types. In this study, we further demonstrate that RAB38/NY-MEL-1 is strongly immunogenic, leading to spontaneous antibody responses in a significant proportion of melanoma patients. The immune response occurs solely in malignant melanoma patients and was not detected in patients with other diseases, such as vitiligo, affecting melanocytes. Fine analysis of the spontaneous anti-RAB38/NY-MEL-1 antibody response reveals a polyclonal B cell recognition targeting various epitopes, although a dominant immunogenic region was preferentially recognized. Interestingly, our data indicate that this recognition is not rigid in the course of a patient’s response, as the dominant epitope changes during the disease evolution. Implications for the understanding of spontaneous humoral immune responses are discussed.

Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242CrossRefPubMed

Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO, Tsang S, Williamson B, Stockert E, Pfreundschuh M, Old LJ (1997) A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA 94:1914–1918PubMedCrossRef

Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148CrossRefPubMed

Fensterle J, Becker JC, Potapenko T, Heimbach V, Vetter CS, Brocker EB, Rapp UR (2004) B-Raf specific antibody responses in melanoma patients. BMC Cancer 4:62CrossRefPubMed

Fishman P, Merimski O, Baharav E, Shoenfeld Y (1997) Autoantibodies to tyrosinase: the bridge between melanoma and vitiligo. Cancer 79:1461–1464CrossRefPubMed

Gnjatic S, Atanackovic D, Jager E, Matsuo M, Selvakumar A, Altorki NK, Maki RG, Dupont B, Ritter G, Chen YT, et al (2003) Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc Natl Acad Sci USA 100:8862–8867CrossRefPubMed

Huang SK, Okamoto T, Morton DL, Hoon DS (1998) Antibody responses to melanoma/melanocyte autoantigens in melanoma patients. J Invest Dermatol 111:662–667CrossRefPubMed

Iwamoto S, Burrows RC, Grossniklaus HE, Orcutt J, Kalina RE, Boehm M, Bothwell MA, Schmidt R (2002) Immunophenotype of conjunctival melanomas: comparisons with uveal and cutaneous melanomas. Arch Ophthalmol 120:1625–1629PubMed

Jager D, Stockert E, Jager E, Gure AO, Scanlan MJ, Knuth A, Old LJ, Chen YT (2000) Serological cloning of a melanocyte rab guanosine 5′-triphosphate-binding protein and a chromosome condensation protein from a melanoma complementary DNA library. Cancer Res 60:3584–3591PubMed

10.

Jager D, Taverna C, Zippelius A, Knuth A (2004) Identification of tumor antigens as potential target antigens for immunotherapy by serological expression cloning. Cancer Immunol Immunother 53:144–147CrossRefPubMed

11.

Jager E, Gnjatic S, Nagata Y, Stockert E, Jager D, Karbach J, Neumann A, Rieckenberg J, Chen YT, Ritter G, et al (2000) Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. Proc Natl Acad Sci USA 97:12198–12203PubMedCrossRef

12.

Jager E, Ringhoffer M, Arand M, Karbach J, Jager D, Ilsemann C, Hagedorn M, Oesch F, Knuth A (1996) Cytolytic T cell reactivity against melanoma-associated differentiation antigens in peripheral blood of melanoma patients and healthy individuals. Melanoma Res 6:419–425PubMedCrossRef

13.

Kemp EH, Waterman EA, Weetman AP (2001) Immunological pathomechanisms in vitiligo. Expert Rev Mol Med 2001:1–22CrossRefPubMed

14.

Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157:105–132CrossRefPubMed

15.

Lins L, Thomas A, Brasseur R (2003) Analysis of accessible surface of residues in proteins. Protein Sci 12:1406–1417CrossRefPubMed

16.

Loftus SK, Larson DM, Baxter LL, Antonellis A, Chen Y, Wu X, Jiang Y, Bittner M, Hammer JA III, Pavan WJ (2002) Mutation of melanosome protein RAB38 in chocolate mice. Proc Natl Acad Sci USA 99:4471–4476CrossRefPubMed

17.

Merimsky O, Baharav E, Shoenfeld Y, Chaitchik S, Tsigelman R, Cohen-Aloro D, Fishman P (1996) Anti-tyrosinase antibodies in malignant melanoma. Cancer Immunol Immunother 42:297–302CrossRefPubMed

18.

Osanai K, Iguchi M, Takahashi K, Nambu Y, Sakuma T, Toga H, Ohya N, Shimizu H, Fisher JH, Voelker DR (2001) Expression and localization of a novel Rab small G protein (Rab38) in the rat lung. Am J Pathol 158:1665–1675PubMed

19.

Osanai K, Takahashi K, Nakamura K, Takahashi M, Ishigaki M, Sakuma T, Toga H, Suzuki T, Voelker DR (2005) Expression and characterization of Rab38, a new member of the Rab small G protein family. Biol Chem 386:143–153CrossRefPubMed

20.

Parker JM, Guo D, Hodges RS (1986) New hydrophilicity scale derived from high-performance liquid chromatography peptide retention data: correlation of predicted surface residues with antigenicity and X-ray-derived accessible sites. Biochemistry 25:5425–5432CrossRefPubMed

21.

Pereira-Leal JB, Seabra MC (2001) Evolution of the Rab family of small GTP-binding proteins. J Mol Biol 313:889–901CrossRefPubMed

22.

Pupa SM, Menard S, Andreola S, Colnaghi MI (1993) Antibody response against the c-erbB-2 oncoprotein in breast carcinoma patients. Cancer Res 53:5864–5866PubMed

23.

Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M (1995) Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci USA 92:11810–11813PubMedCrossRef

24.

Scanlan MJ, Simpson AJ, Old LJ (2004) The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4:1PubMed

25.

Schauer U, Stemberg F, Rieger CH, Buttner W, Borte M, Schubert S, Mollers H, Riedel F, Herz U, Renz H, Herzog W (2003) Levels of antibodies specific to tetanus toxoid, Haemophilus influenzae type b, and pneumococcal capsular polysaccharide in healthy children and adults. Clin Diagn Lab Immunol 10:202–207CrossRefPubMed

26.

Stockert E, Jager E, Chen YT, Scanlan MJ, Gout I, Karbach J, Arand M, Knuth A, Old LJ (1998) A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp Med 187:1349–1354CrossRefPubMed

27.

Takahashi M, Chen W, Byrd DR, Disis ML, Huseby ES, Qin H, McCahill L, Nelson H, Shimada H, Okuno K, et al (1995) Antibody to ras proteins in patients with colon cancer. Clin Cancer Res 1:1071–1077PubMed

28.

Van den Eynde BJ, van der Bruggen P (1997) T cell defined tumor antigens. Curr Opin Immunol 9:684–693CrossRefPubMed

29.

Winter SF, Minna JD, Johnson BE, Takahashi T, Gazdar AF, Carbone DP (1992) Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation. Cancer Res 52:4168–4174PubMed

30.

Yamamoto A, Shimizu E, Ogura T, Sone S (1996) Detection of auto-antibodies against L-myc oncogene products in sera from lung cancer patients. Int J Cancer 69:283–289CrossRefPubMed

31.

Zeng G, Aldridge ME, Wang Y, Pantuck AJ, Wang AY, Liu YX, Han Y, Yuan YH, Robbins PF, Dubinett SM, et al (2005) Dominant B cell epitope from NY-ESO-1 recognized by sera from a wide spectrum of cancer patients: implications as a potential biomarker. Int J Cancer 114:268–273CrossRefPubMed

32.

Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, Rimoldi D, Guillaume P, Meidenbauer N, Mackensen A, et al (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64:2865–2873CrossRefPubMed

Title: Melanocyte differentiation antigen RAB38/NY-MEL-1 induces frequent antibody responses exclusively in melanoma patients
Authors: Alfred Zippelius
Asma Gati
Tammo Bartnick
Senta Walton
Bernhard Odermatt
Elke Jaeger
Reinhold Dummer
Mirjana Urosevic
Valeriy Filonenko
Kazuhiro Osanai
Holger Moch
Yao-Tseng Chen
Lloyd J. Old
Alexander Knuth
Dirk Jaeger
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 2/2007
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0177-z

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 2/2007

Immunotherapy success in prophylaxis cannot predict therapy: prime-boost vaccination against the 5T4 oncofoetal antigen

Lack of tumor recognition by cytolytic T lymphocyte clones recognizing peptide 195–203 encoded by gene MAGE-A3 and presented by HLA-A24 molecules

Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice

Induction of an effective anti-tumor immune response and tumor regression by combined administration of IL-18 and Apoptin

The strange case of TGN1412

Immune selective pressure and HLA class I antigen defects in malignant lesions

Keynote webinar | Spotlight on antibody–drug conjugates in cancer