Skip to main content

Advertisement

SpringerLink
Log in

Natural killer (NK):dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity

  • UNIVERSITY OF PITTSBURGH IMMUNOLOGY 2011
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Tumor antigen (TA)-targeted monoclonal antibodies (mAb), trastuzumab, cetuximab, panitumumab, and rituximab, have been among the most successful new therapies in the present generation. Clinical activity is observed as a single agent, or in combination with radiotherapy or chemotherapy, against metastatic colorectal cancer, head and neck cancer, breast cancer, and follicular lymphoma. However, the activity is seen only in a minority of patients. Thus, an intense need exists to define the mechanism of action of these immunoactive mAb. Here, we discuss some of the likely immunological events that occur in treated patients: antibody-dependent cellular cytotoxicity (ADCC), cross talk among immune cells including NK cells and dendritic cells (DCs), and generation of TA-specific T lymphocyte responses. We present evidence supporting the induction of “NK:DC cross talk,” leading to priming of TA-specific cellular immunity. These observations show that mAb-mediated NK cell activation can be greatly enhanced by the action of stimulatory cytokines and surface molecules on maturing DC and that NK:DC interaction facilitates the recruitment of both NK cells and DC to the tumor site(s). The cooperative, reciprocal stimulatory activity of both NK cells and DC can modulate both the innate immune response in the local tumor microenvironment and the adaptive immune response in secondary lymphoid organs. These events likely contribute to clinical activity, as well as provide a potential biomarker of response to mAb therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ferris RL, Jaffe EM, Ferrone S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoscape. J Clin Oncol. 2010;28(28):4390–9.

    Article  PubMed  CAS  Google Scholar 

  2. Weng WK, Czerwinski D, Timmerman J, et al. Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype. J Clin Oncol. 2004;22:4717–24.

    Article  PubMed  CAS  Google Scholar 

  3. Musolino A, Naldi N, Bortesi B, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008;26:1789–96.

    Article  PubMed  CAS  Google Scholar 

  4. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940–7.

    Article  PubMed  CAS  Google Scholar 

  5. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78.

    Article  PubMed  CAS  Google Scholar 

  6. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27.

    Article  PubMed  CAS  Google Scholar 

  7. Lim SH, Beers SA, French RR, et al. Anti-CD20 monoclonal antibodies—historical and future perspectives. Haematologica. 2009;95:135–43.

    Article  PubMed  Google Scholar 

  8. Winter MC, Hancock BW. Ten years of rituximab in NHL. Expert Opin Drug Saf. 2009;8:223–35.

    Article  PubMed  CAS  Google Scholar 

  9. Gill S, Goldberg RM. Cetuximab, and chemotherapy and KRAS status in mCRC. Nat Rev Clin Oncol. 2009;6:379–80.

    Article  PubMed  CAS  Google Scholar 

  10. Spiro H. Cetuximab for metastatic colorectal cancer. N Engl J Med. 2009;361:95.

    Article  PubMed  CAS  Google Scholar 

  11. Adams GP, Weiner LM. Monoclonal antibody therapy for cancer. Nat Biotechnol. 2005;23:1147–57.

    Article  PubMed  CAS  Google Scholar 

  12. Yun CH, Boggon TJ, Li Y, et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007;11:217–27.

    Article  PubMed  CAS  Google Scholar 

  13. Bonavida B. Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions. Oncogene. 2007;26:3629–36.

    Article  PubMed  CAS  Google Scholar 

  14. Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824–32.

    Article  Google Scholar 

  15. Harari PM, Allen GW, Bonner JA. Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol. 2007;25:4057–65.

    Article  PubMed  CAS  Google Scholar 

  16. Weiner LM, Dhodapkar MV, Ferrone S. Monoclonal antibodies for cancer immunotherapy. Lancet. 2009;373(9668):1033–40.

    Article  PubMed  CAS  Google Scholar 

  17. López-Albitero A, Lee SC, Morgan S, Grandis JR, Gooding WE, Ferrone S, Ferris RL. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother. 2009;58(11):1853–64.

    Article  Google Scholar 

  18. Tax WJ, Tamboer WP, Jacobs CW, et al. Role of polymorphic Fc receptor Fc gamma RIIa in cytokine release and adverse effects of murine IgG1 anti-CD3/T cell receptor antibody (WT31). Transplantation. 1997;63:106–12.

    Article  PubMed  CAS  Google Scholar 

  19. Warmerdam PA, van den Herik-Oudijk IE, Parren PW, et al. Interaction of a human Fc gamma RIIb1 (CD32) isoform with murine and human IgG subclasses. Int Immunol. 1993;5:239–47.

    Article  PubMed  CAS  Google Scholar 

  20. Lopez-Albaitero A, Ferris RL. Immune activation by epidermal growth factor receptor specific monoclonal antibody therapy for head and neck cancer. Arch Otolaryngol Head Neck Surg. 2007;133:1277–81.

    Article  PubMed  Google Scholar 

  21. Kurai J, Chikumi H, Hashimoto K, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res. 2007;13:1552–61.

    Article  PubMed  CAS  Google Scholar 

  22. Schneider-Merck T, Lammerts van Bueren JJ, Berger S, Rossen K, van Berkel PH, Derer S, Beyer T, Lohse S, Bleeker WK, Peipp M, Parren PW, van de Winkel JG, Valerius T, Dechant M. Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibody-dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol. 2010;184(1):512–20.

    Article  PubMed  CAS  Google Scholar 

  23. Dhodapkar KM, Krasovsky J, Williamson B, Dhodapkar MV. Antitumor monoclonal antibodies enhance cross-presentation of Cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J Exp Med. 2002;195(1):125–33.

    Article  PubMed  CAS  Google Scholar 

  24. Dhodapkar KM, Kaufman JL, Ehlers M, Banerjee DK, Bonvini E, Koenig S, Steinman RM, Ravetch JV, Dhodapkar MV. Selective blockade of inhibitory Fc gamma receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc Natl Acad Sci USA. 2005;102(8):2910–5.

    Article  PubMed  CAS  Google Scholar 

  25. Banerjee D, Matthews P, Matayeva E, Kaufman JL, Steinman RM, Dhodapkar KM. Enhanced T-cell responses to glioma cells coated with the anti-EGF receptor antibody and targeted to activating Fc gamma Rs on human dendritic cells. J Immunother. 2008;31(2):113–20.

    Article  PubMed  CAS  Google Scholar 

  26. Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J Clin Invest. 2005;115(10):2914–23.

    Article  PubMed  CAS  Google Scholar 

  27. Stagg J, Loi S, Divisekera U, Ngiow SF, Duret H, Yagita H, Teng MW, Smyth MJ. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci USA. 2011;108(17):7142–7.

    Article  PubMed  CAS  Google Scholar 

  28. Taylor C, Hershman D, Shah N, et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin Cancer Res. 2007;13:5133–43.

    Article  PubMed  CAS  Google Scholar 

  29. Srivastava RM, Khar A. Dendritic cells and their receptors in antitumor immune response. Curr Mol Med. 2009;9(6):708–24.

    Article  PubMed  CAS  Google Scholar 

  30. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313(5787):670–3.

    Article  PubMed  CAS  Google Scholar 

  31. Márquez ME, Millet C, Stekman H, Conesa A, Deglesne PA, Toro F, Sanctis JD, Blanca I. CD16 cross-linking induces increased expression of CD56 and production of IL-12 in peripheral NK cells. Cell Immunol. 2010;264(1):86–92.

    Article  PubMed  Google Scholar 

  32. López-Albaitero A, Maillard RB, Hackman T, Andrade Filho PA, Wang X, Gooding W, Ferrone S, Kalinski P, Ferris RL. Maturation pathways of dendritic cells determine TAP1 and TAP2 levels and cross-presenting function. J Immunother. 2009;32(5):465–73.

    Article  PubMed  Google Scholar 

  33. Sharafinski ME, Ferris RL, Ferrone S, Grandis JR. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck. 2010;32(10):1412–21.

    Article  PubMed  Google Scholar 

  34. Roda JM, Joshi T, Butchar JP, et al. The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clin Cancer Res. 2007;13:6419–28.

    Article  PubMed  CAS  Google Scholar 

  35. Roda JM, Parihar R, Magro C, et al. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Cancer Res. 2006;66:517–26.

    Article  PubMed  CAS  Google Scholar 

  36. Kalinski P, Mailliard RB, Giermasz A, et al. Natural killer-dendritic cell cross-talk in cancer immunotherapy. Expert Opin Biol Ther. 2005;5:1303–15.

    Article  PubMed  CAS  Google Scholar 

  37. Mailliard RB, Son YI, Redlinger R, et al. Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol. 2003;171:2366–73.

    PubMed  CAS  Google Scholar 

  38. Roberti MP, Barrio MM, Bravo AI, Rocca YS, Arriaga JM, Bianchini M, Mordoh J, Levy EM. IL-15 and IL-2 increase Cetuximab-mediated cellular cytotoxicity against triple negative breast cancer cell lines expressing EGFR. Breast Cancer Res Treat. 2011. doi: 10.1007/s10549-011-1360-2.

  39. Watanabe M, Kono K, Kawaguchi Y, Mizukami Y, Mimura K, Maruyama T, Fujii H. Interleukin-21 can efficiently restore impaired antibody-dependent cell-mediated cytotoxicity in patients with oesophageal squamous cell carcinoma. Br J Cancer. 2010;102(3):520–9.

    Article  PubMed  CAS  Google Scholar 

  40. Hara M, Nakanishi H, Tsujimura K, Matsui M, Yatabe Y, Manabe T, Tatematsu M. Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody-dependent cellular cytotoxicity. Cancer Sci. 2008;99(7):1471–8.

    Article  PubMed  CAS  Google Scholar 

  41. Wehner R, Dietze K, Bachmann M, Schmitz M. The bidirectional crosstalk between human dendritic cells and natural killer cells. J Innate Immun. 2011;3(3):258–63.

    Article  PubMed  CAS  Google Scholar 

  42. el-Shami K, Tirosh B, Bar-Haim E, et al. MHC class I-restricted epitope spreading in the context of tumor rejection following vaccination with a single immunodominant CTL epitope. Eur J Immunol. 1999;29:3295–301.

    Article  PubMed  CAS  Google Scholar 

  43. Mailliard RB, Alber SM, Shen H, et al. IL-18-induced CD83+CCR7+ NK helper cells. J Exp Med. 2005;202:941–53.

    Article  PubMed  CAS  Google Scholar 

  44. Brady J, Carotta S, Thong RP, Chan CJ, Hayakawa Y, Smyth MJ, Nutt SL. The interactions of multiple cytokines control NK cell maturation. J Immunol. 2010;185(11):6679–88.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA

    Steve C. Lee, Raghvendra M. Srivastava, Andrés López-Albaitero & Robert L. Ferris

  2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Soldano Ferrone

  3. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Soldano Ferrone & Robert L. Ferris

  4. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Soldano Ferrone & Robert L. Ferris

  5. The Hillman Cancer Center Research Pavilion, 5117 Centre Avenue, Room 2.26b, Pittsburgh, PA, 15213, USA

    Robert L. Ferris

Authors
  1. Steve C. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raghvendra M. Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrés López-Albaitero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Soldano Ferrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert L. Ferris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert L. Ferris.

Additional information

Steve C. Lee and Raghvendra M. Srivastava contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, S.C., Srivastava, R.M., López-Albaitero, A. et al. Natural killer (NK):dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res 50, 248–254 (2011). https://doi.org/10.1007/s12026-011-8231-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-011-8231-0

Keywords

Search

Navigation