Prostate Cancer and Immunoproteome: Awakening and Reprogramming the Guardian Angels

  • Ammad Ahmad Farooqi
  • Sundas Fayyaz
  • Muhammad Zahid Qureshi
  • Sadia Rashid


Prostate cancer is a life-threatening molecular disorder that is undruggable to date because of stumbling blocks in the standardization of therapy. An emerging framework of research is addressing how pathways that are derailed during tumorigenesis are linked to immunological responses, which are instrumental in immunosurveillance of cancer. However, interestingly, cancer cells circumvent such immunosurveillance through development of poorly immunogenic tumor cell variants (immunoselection) and through subversion of the immunological nanomachinery (immunosubversion). Detailed mechanistic insights of molecular specificities that regulate natural killer (NK) cell function suggest that it might be promising to design NK cell-based immunotherapeutic interventions against prostate cancer. Here, we elucidate evidence for NK cell targeting of prostate cancer proteome and address critical questions that, in our view, need thoughtfulness for the development of successful NK cell-based therapies. This review also disproves our contemporary understanding of the versatile regulators of DNA damage repair (ATM, ATR) that trigger cell surface expression of NKG2D ligands and consequent elimination of the tumor cells by NK cells and other lymphocytes that express NK cell receptors. Substantial fraction of information has been generated that guarantees productive future for this technology as more optimized constructs, better trial designs, and improved platforms are being brought from benchtop to bedside.


Prostate cancer Immunoproteome DNA damage Major histocompatibility complex proteins 


  1. Ardolino M, Zingoni A, Cerboni C et al (2011) DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction. Blood 117:4778–4786PubMedCrossRefGoogle Scholar
  2. Butler JE, Moore MB, Presnell SR et al (2009) Proteasome regulation of ULBP1 transcription. J Immunol 182:6600–6609PubMedCrossRefGoogle Scholar
  3. Cao Y, Lan Y, Qian J et al (2011) Targeting cell surface β2-microglobulin by pentameric IgM antibodies. Br J Haematol 154:111–121PubMedCrossRefGoogle Scholar
  4. Cerboni C, Zingoni A, Cippitelli M et al (2007) Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK-cell lysis. Blood 110:606–615PubMedCrossRefGoogle Scholar
  5. Chakraborty M, Wansley EK, Carrasquillo JA et al (2008) The use of chelated radionuclide (samarium-153-ethylenediaminetetramethylenephosphonate) to modulate phenotype of tumor cells and enhance T cell-mediated killing. Clin Cancer Res 14:4241–4249PubMedCrossRefGoogle Scholar
  6. Chávez-Blanco A, De la Cruz-Hernández E, Domínguez GI et al (2011) Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate. Int J Oncol 39:1491–1499PubMedGoogle Scholar
  7. Elkord E, Williams PE, Kynaston H et al (2005) Differential CTLs specific for prostate-specific antigen in healthy donors and patients with prostate cancer. Int Immunol 17:1315–1325PubMedCrossRefGoogle Scholar
  8. Epel M, Carmi I, Soueid-Baumgarten S et al (2008) Targeting TARP, a novel breast and prostate tumor-associated antigen, with T cell receptor-like human recombinant antibodies. Eur J Immunol 38:1706–1720PubMedCrossRefGoogle Scholar
  9. Fortmüller K, Alt K, Gierschner D et al (2011) Effective targeting of prostate cancer by lymphocytes redirected by a PSMA  ×  CD3 bispecific single-chain diabody. Prostate 71:588–596PubMedCrossRefGoogle Scholar
  10. Fujii R, Iwahashi M, Kikkawa K et al (2009) Bacillus Calmette-Guérin cell-wall skeleton enhances the killing activity of cytotoxic lymphocyte-activated human dendritic cells transduced with the prostate-specific antigen gene. BJU Int 104:1766–1773PubMedCrossRefGoogle Scholar
  11. Garcia-Hernandez Mde L, Gray A, Hubby B et al (2008) Prostate stem cell antigen vaccination induces a long-term protective immune response against prostate cancer in the absence of autoimmunity. Cancer Res 68:861–869PubMedCrossRefGoogle Scholar
  12. Guerra N, Tan YX, Joncker NT et al (2008) NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28:571–580PubMedCrossRefGoogle Scholar
  13. Humphreys RE, Hillman GG, von Hofe E et al (2004) Forcing tumor cells to present their own tumor antigens to the immune system: a necessary design for an efficient tumor immunotherapy. Cell Mol Immunol 1:180–185PubMedGoogle Scholar
  14. Jachimowicz RD, Fracasso G, Yazaki PJ et al (2011) Induction of in vitro and in vivo NK cell cytotoxicity using high-avidity immunoligands targeting prostate-specific membrane antigen in prostate carcinoma. Mol Cancer Ther 10:1036–1045PubMedCrossRefGoogle Scholar
  15. Kandasamy M, Bay BH, Lee YK et al (2011) Lactobacilli secreting a tumor antigen and IL-15 activates neutrophils and dendritic cells and generates cytotoxic T lymphocytes against cancer cells. Cell Immunol 271:89–96PubMedCrossRefGoogle Scholar
  16. Kim S, Lee JB, Lee GK et al (2009) Vaccination with recombinant adenoviruses and dendritic cells expressing prostate-specific antigens is effective in eliciting CTL and suppresses tumor growth in the experimental prostate cancer. Prostate 69:938–948PubMedCrossRefGoogle Scholar
  17. Klyushnenkova EN, Kouiavskaia DV, Berard CA et al (2009) Cutting edge: permissive MHC class II allele changes the pattern of antitumor immune response resulting in failure of tumor rejection. J Immunol 182:1242–1246PubMedGoogle Scholar
  18. Kobayashi H, Nagato T, Sato K et al (2007) Recognition of prostate and melanoma tumor cells by six-transmembrane epithelial antigen of prostate-specific helper T lymphocytes in a human leukocyte antigen class II-restricted manner. Cancer Res 67:5498–5504PubMedCrossRefGoogle Scholar
  19. Kuang Y, Weng X, Liu X et al (2010) Anti-tumor immune response induced by dendritic cells transduced with truncated PSMA IRES 4-1BBL recombinant adenoviruses. Cancer Lett 293:254–262PubMedCrossRefGoogle Scholar
  20. Lemke CD, Graham JB, Lubaroff DM et al (2011) Development of an MHC class I L(d)-restricted PSA peptide-loaded tetramer for detection of PSA-specific CD8 + T cells in the mouse. Prostate Cancer Prostatic Dis 14:118–121PubMedCrossRefGoogle Scholar
  21. Li H, Lakshmikanth T, Garofalo C et al (2011) Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2. Cell Cycle 10:3346–3358PubMedCrossRefGoogle Scholar
  22. Lu X, Ohata K, Kondo Y et al (2010) Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis. Cancer Sci 101:609–615PubMedCrossRefGoogle Scholar
  23. Mahadevan M, Liu Y, You C et al (2007) Generation of robust cytotoxic T lymphocytes against prostate specific antigen by transduction of dendritic cells using protein and recombinant adeno-associated virus. Cancer Immunol Immunother 56:1615–1624PubMedCrossRefGoogle Scholar
  24. Mitra N, Banda K, Altheide TK et al (2011) SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas. J Biol Chem 286:23003–23011PubMedCrossRefGoogle Scholar
  25. Nanda NK, Birch L, Greenberg NM et al (2006) MHC class I and class II molecules are expressed in both human and mouse prostate tumor microenvironment. Prostate 66:1275–1284PubMedCrossRefGoogle Scholar
  26. Ogbomo H, Michaelis M, Geiler J et al (2010) Tumor cells infected with oncolytic influenza A virus prime natural killer cells for lysis of resistant tumor cells. Med Microbiol Immunol 199:93–101PubMedCrossRefGoogle Scholar
  27. Pastor F, Kolonias D, McNamara JO II et al (2011) Targeting 4-1BB costimulation to disseminated tumor lesions with bi-specific oligonucleotide aptamers. Mol Ther 19:1878–1886PubMedCrossRefGoogle Scholar
  28. Raja Gabaglia C, Diaz de Durana Y, Graham FL et al (2007) Attenuation of the glucocorticoid response during Ad5IL-12 adenovirus vector treatment enhances natural killer cell-mediated killing of MHC class I-negative LNCaP prostate tumors. Cancer Res 67:2290–2297PubMedCrossRefGoogle Scholar
  29. Rodeberg DA, Nuss RA, Elsawa SF et al (2005) Recognition of six-transmembrane epithelial antigen of the prostate-expressing tumor cells by peptide antigen-induced cytotoxic T lymphocytes. Clin Cancer Res 11:4545–4552PubMedCrossRefGoogle Scholar
  30. Smith HA, Cronk RJ, Lang JM et al (2011) Expression and immunotherapeutic targeting of the SSX family of cancer-testis antigens in prostate cancer. Cancer Res 71:6785–6795PubMedCrossRefGoogle Scholar
  31. Soriani A, Zingoni A, Cerboni C et al (2009) ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113:3503–3511PubMedCrossRefGoogle Scholar
  32. Tabata K, Kurosaka S, Watanabe M et al (2011) Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model. Gene Ther 18:969–978PubMedCrossRefGoogle Scholar
  33. Tang KF, He CX, Zeng GL et al (2008a) Induction of MHC class I-related chain B (MICB) by 5-aza-2′-deoxycytidine. Biochem Biophys Res Commun 370:578–583PubMedCrossRefGoogle Scholar
  34. Tang KF, Ren H, Cao J et al (2008b) Decreased dicer expression elicits DNA damage and up-regulation of MICA and MICB. J Cell Biol 182:233–239PubMedCrossRefGoogle Scholar
  35. Turkeri L, Onol FF, Ozyurek M (2010) Tumor specific cytotoxicity and telomerase down-regulation in prostate cancer by autologous dendritic cells loaded with whole tumor cell antigens. Urol Oncol 28:290–295PubMedCrossRefGoogle Scholar
  36. Varghese S, Rabkin SD, Liu R et al (2006) Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther 13:253–265PubMedCrossRefGoogle Scholar
  37. Vittes GE, Harden EL, Ottensmeier CH et al (2011) DNA fusion gene vaccines induce cytotoxic T-cell attack on naturally processed peptides of human prostate-specific membrane antigen. Eur J Immunol 41:2447–2456PubMedCrossRefGoogle Scholar
  38. Waeckerle-Men Y, Uetz-von Allmen E, Fopp M et al (2006) Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma. Cancer Immunol Immunother 55:1524–1533PubMedCrossRefGoogle Scholar
  39. Wu JD, Atteridge CL, Wang X et al (2009a) Obstructing shedding of the immunostimulatory MHC class I chain-related gene B prevents tumor formation. Clin Cancer Res 15:632–640PubMedCrossRefGoogle Scholar
  40. Wu JF, Zeng GL, Shen W et al (2009b) Up-regulation of major histocompatibility complex class I-related molecules A (MICA) induced by 5-aza-2′-deoxycytidine. Zhonghua Gan Zang Bing Za Zhi 17:675–678PubMedGoogle Scholar
  41. Zhang X, Yu C, Zhao J et al (2007) Vaccination with a DNA vaccine based on human PSCA and HSP70 adjuvant enhances the antigen-specific CD8 + T-cell response and inhibits the PSCA + tumors growth in mice. J Gene Med 9:715–726PubMedCrossRefGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2012

Authors and Affiliations

  • Ammad Ahmad Farooqi
    • 1
  • Sundas Fayyaz
    • 1
  • Muhammad Zahid Qureshi
    • 2
  • Sadia Rashid
    • 3
  1. 1.Laboratory for Translational Oncology and Personalized MedicineRashid Latif Medical College (RLMC)LahorePakistan
  2. 2.Biochemistry Lab, Department of ChemistryGC UniversityLahorePakistan
  3. 3.NUST Centre of Virology and Immunology (NCVI)National University of Science and TechnologyIslamabadPakistan

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