Cancer Immunology, Immunotherapy

, Volume 59, Issue 9, pp 1313–1323 | Cite as

Antibody responses to galectin-8, TARP and TRAP1 in prostate cancer patients treated with a GM-CSF-secreting cellular immunotherapy

  • Minh C. Nguyen
  • Guang Huan Tu
  • Kathryn E. Koprivnikar
  • Melissa Gonzalez-Edick
  • Karin U. Jooss
  • Thomas C. Harding
Original Article


A critical factor in clinical development of cancer immunotherapies is the identification of tumor-associated antigens that may be related to immunotherapy potency. In this study, protein microarrays containing >8,000 human proteins were screened with serum from prostate cancer patients (N = 13) before and after treatment with a granulocyte–macrophage colony-stimulating factor (GM-CSF)-secreting whole cell immunotherapy. Thirty-three proteins were identified that displayed significantly elevated (P ≤ 0.05) signals in post-treatment samples, including three proteins that have previously been associated with prostate carcinogenesis, galectin-8, T-cell alternative reading frame protein (TARP) and TNF-receptor-associated protein 1 (TRAP1). Expanded analysis of antibody induction in metastatic, castration-resistant prostate cancer (mCRPC) patients (N = 92) from two phase 1/2 trials of prostate cancer immunotherapy, G-9803 and G-0010, indicated a significant (P = 0.03) association of TARP antibody induction and median survival time (MST). Antibody induction to TARP was also significantly correlated (P = 0.036) with an increase in prostate-specific antigen doubling time (PSADT) in patients with a biochemical (PSA) recurrence following prostatectomy or radiation therapy (N = 19) from in a previous phase 1/2 trial of prostate cancer immunotherapy, G-9802. RNA and protein encoding TARP and TRAP1 was up-regulated in prostate cancer tissue compared to matched normal controls. These preliminary findings suggest that antibody induction to TARP may represent a possible biomarker for treatment response to GM-CSF secreting cellular immunotherapy in prostate cancer patients and demonstrates the utility of using protein microarrays for the high-throughput screening of patient-derived antibody responses.


Immunotherapy Tumor antigen Autoantibody Protein microarray Prostate cancer Biomarker 



Research support was provided by Cell Genesys, Inc., South San Francisco, CA.

Conflict of interest statement

Authors MN, GT, KK, ME, KJ and TH received financial and stock support from Cell Genesys, Inc. as their primary source of employment.

Supplementary material

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Supplementary material 1 (DOC 43 kb)
262_2010_858_MOESM2_ESM.doc (30 kb)
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262_2010_858_MOESM3_ESM.ppt (470 kb)
Supplementary material 1 (DOC 469 kb)


  1. 1.
    Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF, Jones LW (1979) Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol 17:16–23PubMedGoogle Scholar
  2. 2.
    Horoszewicz JS et al (1980) The LNCaP cell line—a new model for studies on human prostatic carcinoma. Prog Clin Biol Res 37:115–132PubMedGoogle Scholar
  3. 3.
    Chang DZ et al (2004) Granulocyte-macrophage colony stimulating factor: an adjuvant for cancer vaccines. Hematology 9:207–215CrossRefPubMedGoogle Scholar
  4. 4.
    Fleetwood AJ, Cook AD, Hamilton JA (2005) Functions of granulocyte-macrophage colony-stimulating factor. Crit Rev Immunol 25:405–428CrossRefPubMedGoogle Scholar
  5. 5.
    Urba WJ et al (2008) Treatment of biochemical recurrence of prostate cancer with granulocyte-macrophage colony-stimulating factor secreting, allogeneic. Cellular Immunotherapy J Urol 180:2011–2017Google Scholar
  6. 6.
    Small EJ et al (2007) Granulocyte macrophage colony-stimulating factor–secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clin Cancer Res 13:3883–3891CrossRefPubMedGoogle Scholar
  7. 7.
    Higano CS et al (2008) Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer. Cancer 113:975–984CrossRefPubMedGoogle Scholar
  8. 8.
    Higano C et al (2009) A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC). American Society of Clinical Oncology’s Genitourinary Cancer Symposium, Orlando, Florida LBA150Google Scholar
  9. 9.
    Halabi S et al (2003) Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 21:1232–1237CrossRefPubMedGoogle Scholar
  10. 10.
    Su ZZ et al (1996) Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family. Proc Natl Acad Sci USA 93:7252–7257CrossRefPubMedGoogle Scholar
  11. 11.
    Bidon-Wagner N, Le Pennec JP (2004) Human galectin-8 isoforms and cancer. Glycoconj J 19:557–563CrossRefPubMedGoogle Scholar
  12. 12.
    Essand M et al (1999) High expression of a specific T-cell receptor gamma transcript in epithelial cells of the prostate. Proc Natl Acad Sci USA 96:9287–9292CrossRefPubMedGoogle Scholar
  13. 13.
    Wolfgang CD, Essand M, Vincent JJ, Lee B, Pastan I (2000) TARP: a nuclear protein expressed in prostate and breast cancer cells derived from an alternate reading frame of the T cell receptor gamma chain locus. Proc Natl Acad Sci USA 197:9437–9442CrossRefGoogle Scholar
  14. 14.
    Wolfgang CD, Essand M, Lee B, Pastan I (2001) T-cell receptor gamma chain alternate reading frame protein (TARP) expression in prostate cancer cells leads to an increased growth rate and induction of caveolins and amphiregulin. Cancer Res 61:8122–8126PubMedGoogle Scholar
  15. 15.
    Leav I et al (2010) Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. Am J Pathol 176:393–401CrossRefPubMedGoogle Scholar
  16. 16.
    Maeda H et al (2004) The T cell receptor gamma chain alternate reading frame protein (TARP), a prostate-specific protein localized in mitochondria. J Biol Chem 279:24561–24568CrossRefPubMedGoogle Scholar
  17. 17.
    Imai Y et al (2002) Cloning and characterization of the highly expressed ETEA gene from blood cells of atopic dermatitis patients. Biochem Biophys Res Commun 297:1282–1290CrossRefPubMedGoogle Scholar
  18. 18.
    Domagala A, Kurpisz M (2001) CD52 antigen—a review. Med Sci Monit 7:325–331PubMedGoogle Scholar
  19. 19.
    Gao Y et al (2006) Activation of the selenoprotein SEPS1 gene expression by pro-inflammatory cytokines in HepG2 cells. Cytokine 33:246–251CrossRefPubMedGoogle Scholar
  20. 20.
    Mamane Y et al (1999) Interferon regulatory factors: the next generation. Gene 237:1–14CrossRefPubMedGoogle Scholar
  21. 21.
    Hartmann E et al (1993) A tetrameric complex of membrane proteins in the endoplasmic reticulum. Eur J Biochem 214:375–381CrossRefPubMedGoogle Scholar
  22. 22.
    Song HY, Dunbar JD, Zhang YX, Guo D, Donner DB (1995) Identification of a protein with homology to hsp90 that binds the type 1 tumor necrosis factor receptor. J Biol Chem 270:3574–3581CrossRefPubMedGoogle Scholar
  23. 23.
    Oda Y et al (2006) Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 172:383–393CrossRefPubMedGoogle Scholar
  24. 24.
    Hjelmqvist L et al (2002) ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol 3:1–16CrossRefGoogle Scholar
  25. 25.
    Felts SJ et al (2000) The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem 275:3305–3312CrossRefPubMedGoogle Scholar
  26. 26.
    Houtkooper RH, Vaz FM (2008) Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci 65:2493–2506CrossRefPubMedGoogle Scholar
  27. 27.
    Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429:841–847CrossRefPubMedGoogle Scholar
  28. 28.
    Cheng WS, Giandomenico V, Pastan I, Essand M (2003) Characterization of the androgen-regulated prostate-specific T cell receptor gamma-chain alternate reading frame protein (TARP) promoter. Endocrinology 144:3433–3440CrossRefPubMedGoogle Scholar
  29. 29.
    Schlomm T et al (2005) Extraction and processing of high quality RNA from impalpable and macroscopically invisible prostate cancer for microarray gene expression analysis. Int J Oncol 27:713–720PubMedGoogle Scholar
  30. 30.
    Carlsson B, Tötterman TH, Essand M (2004) Generation of cytotoxic T lymphocytes specific for the prostate and breast tissue antigen TARP. Prostate 61:161–170CrossRefPubMedGoogle Scholar
  31. 31.
    Oh S et al (2004) Human CTLs to wild-type and enhanced epitopes of a novel prostate and breast tumor-associated protein, TARP, lyse human breast cancer cells. Cancer Res 64:2610–2618CrossRefPubMedGoogle Scholar
  32. 32.
    Kobayashi H et al (2005) Recognition of prostate and breast tumor cells by helper T lymphocytes specific for a prostate and breast tumor-associated antigen, TARP. Clin Cancer Res 11:3869–3878CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Minh C. Nguyen
    • 1
  • Guang Huan Tu
    • 1
  • Kathryn E. Koprivnikar
    • 1
  • Melissa Gonzalez-Edick
    • 1
  • Karin U. Jooss
    • 1
  • Thomas C. Harding
    • 1
    • 2
  1. 1.Cell Genesys Inc.South San FranciscoUSA
  2. 2.Five Prime Therapeutics, Inc.San FranciscoUSA

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