Cancer Immunology, Immunotherapy

, Volume 55, Issue 9, pp 1122–1131 | Cite as

NK cell activation by dendritic cell vaccine: a mechanism of action for clinical activity

  • Takuya Osada
  • Timothy Clay
  • Amy Hobeika
  • H. Kim Lyerly
  • Michael A. Morse
Original Article


Recent reports revealed that dendritic cell (DC)–natural killer (NK) cell interaction plays an important role in tumor immunity, but few DC vaccine studies have attempted to evaluate the non-specific, yet potentially clinically relevant, NK response to immunization. In this study, we first analyzed in vitro activation of NK cells by DCs similar to those used in clinical trials. Subsequently, NK cell responses were analyzed in a phase I clinical trial of a vaccine consisting of autologous DCs loaded with a fowlpox vector encoding CEA. The data were compared with the clinical outcome of the patients. DC enhances NK activity in vitro, partly by sustaining NK cell survival and by enhancing the expression of NK-activating receptors, including NKp46 and NKG2D. Among nine patients in our clinical trial, NK cytolytic activity increased in four (range 2.5–5 times greater lytic activity) including three who had increased NK cell frequency, was stable in two and decreased in three. NKp46 and NKG2D expression showed a good correlation with the patients’ NK activity. When patients were grouped by clinical activity (stable disease/no evidence of disease (stable/NE, n=5) vs progressive disease (N=4) at 3 months), the majority in the stable/NE group had increases in NK activity (P=0.016). Anti-CEA T cell response was enhanced in all the nine patients analyzed, but was not significantly different between the two groups (P=0.14). Thus, NK responses following DC vaccination may correlate more closely with clinical outcome than do T cell responses. Monitoring of NK response during vaccine studies should be routinely performed.


Natural killer cell Dendritic cell Vaccine Clinical trial 


  1. 1.
    Morse MA, Clay TM, Hobeika AC, Osada T, Khan S, Chui S, Niedzwiecki D, Panicali D, Schlom J, Lyerly HK (2005) Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules. Clin Cancer Res 11:3017–3024CrossRefPubMedGoogle Scholar
  2. 2.
    Yokoyama WM, Kim S, French AR (2004) The dynamic life of natural killer cells. Annu Rev Immunol 22:405–429CrossRefPubMedGoogle Scholar
  3. 3.
    Glas R, Franksson L, Une C, Eloranta ML, Ohlen C, Orn A, Karre K (2000) Recruitment and activation of natural killer (NK) cells in vivo determined by the target cell phenotype. An adaptive component of NK cell-mediated responses. J Exp Med 191:129–138CrossRefPubMedGoogle Scholar
  4. 4.
    Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, Perricaudet M, Tursz T, Maraskovsky E, Zitvogel L (1999) Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 5:405–411CrossRefPubMedGoogle Scholar
  5. 5.
    Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195:343–351CrossRefPubMedGoogle Scholar
  6. 6.
    Piccioli D, Sbrana S, Melandri E, Valiante NM (2002) Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 195:335–341CrossRefPubMedGoogle Scholar
  7. 7.
    Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195:327–333CrossRefPubMedGoogle Scholar
  8. 8.
    Raulet DH (2004) Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 5:996–1002CrossRefPubMedGoogle Scholar
  9. 9.
    Kim A, Noh YW, Kim KD, Jang YS, Choe YK, Lim JS (2004) Activated natural killer cell-mediated immunity is required for the inhibition of tumor metastasis by dendritic cell vaccination. Exp Mol Med 36:428–443PubMedGoogle Scholar
  10. 10.
    Parajuli P, Mathupala S, Sloan AE (2004) Systematic comparison of dendritic cell-based immunotherapeutic strategies for malignant gliomas: in vitro induction of cytolytic and natural killer-like T cells. Neurosurgery 55:1194–1204CrossRefPubMedGoogle Scholar
  11. 11.
    Carbone E, Terrazzano G, Ruggiero G, Zanzi D, Ottaiano A, Manzo C, Karre K, Zappacosta S (1999) Recognition of autologous dendritic cells by human NK cells. Eur J Immunol 29:4022–4029CrossRefPubMedGoogle Scholar
  12. 12.
    Wilson JL, Heffler LC, Charo J, Scheynius A, Bejarano MT, Ljunggren HG (1999) Targeting of human dendritic cells by autologous NK cells. J Immunol 163:6365–6370PubMedGoogle Scholar
  13. 13.
    Gerosa F, Gobbi A, Zorzi P, Burg S, Briere F, Carra G, Trinchieri G (2005) The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J Immunol 174:727–734PubMedGoogle Scholar
  14. 14.
    van den Broeke LT, Daschbach E, Thomas EK, Andringa G, Berzofsky JA (2003) Dendritic cell-induced activation of adaptive and innate antitumor immunity. J Immunol 171:5842–5852PubMedGoogle Scholar
  15. 15.
    Adam C, King S, Allgeier T, Braumuller H, Luking C, Mysliwietz J, Kriegeskorte A, Busch DH, Rocken M, Mocikat R (2005) DC–NK cell cross-talk as a novel CD4+ T cell-independent pathway for antitumor CTL induction. Blood Mar 15 [Epub ahead of print]Google Scholar
  16. 16.
    Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, Abraham R, Juji T, Macfarlane DJ, Nicol AJ (2004) Therapeutic activation of Va24+Vb11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103:383–389CrossRefPubMedGoogle Scholar
  17. 17.
    Valteau-Couanet D, Leboulaire C, Maincent K, Tournier M, Hartmann O, Benard J, Beaujean F, Boccaccio C, Zitvogel L, Angevin E (2002) Dendritic cells for NK/LAK activation: rationale for multicellular immunotherapy in neuroblastoma patients. Blood 100:2554–2561CrossRefPubMedGoogle Scholar
  18. 18.
    Fehniger TA, Caligiuri MA (2001) Interleukin 15: biology and relevance to human disease. Blood 97:14–32CrossRefPubMedGoogle Scholar
  19. 19.
    Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, Aguila HL, Caligiuri MA (2002) In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 100:3633–3638CrossRefPubMedGoogle Scholar
  20. 20.
    Kalinski P, Giermasz A, Nakamura Y, Basse P, Storkus WJ, Kirkwood JM, Mailliard RB (2005) Helper role of NK cells during the induction of anticancer responses by dendritic cells. Mol Immunol 42:535–539CrossRefPubMedGoogle Scholar
  21. 21.
    Assarsson E, Kambayashi T, Schatzle JD, Cramer SO, von Bonin A, Jensen PE, Ljunggren HG, Chambers BJ (2004) NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions. J Immunol 173:174–180PubMedGoogle Scholar
  22. 22.
    Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH (2002) The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17:19–29CrossRefPubMedGoogle Scholar
  23. 23.
    Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729CrossRefPubMedGoogle Scholar
  24. 24.
    Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL, Phillips JH (1999) An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285:730–732CrossRefPubMedGoogle Scholar
  25. 25.
    Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, Marcenaro E, Accame L, Malaspina A, Biassoni R, Bottino C, Moretta L, Moretta A (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 190:1505–1516CrossRefPubMedGoogle Scholar
  26. 26.
    Vitale M, Bottino C, Sivori S, Sanseverino L, Castriconi R, Marcenaro E, Augugliaro R, Moretta L, Moretta A (1998) NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J Exp Med 187:2065–2072CrossRefPubMedGoogle Scholar
  27. 27.
    Sivori S, Vitale M, Morelli L, Sanseverino L, Augugliaro R, Bottino C, Moretta L, Moretta A (1997) p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med 186:1129–1136CrossRefPubMedGoogle Scholar
  28. 28.
    Spaggiari GM, Carosio R, Pende D, Marcenaro S, Rivera P, Zocchi MR, Moretta L, Poggi A (2001) NK cell-mediated lysis of autologous antigen-presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46. Eur J Immunol 31:1656–1665CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Takuya Osada
    • 1
  • Timothy Clay
    • 1
  • Amy Hobeika
    • 1
  • H. Kim Lyerly
    • 1
  • Michael A. Morse
    • 1
  1. 1.Duke University Medical CenterDurhamUSA

Personalised recommendations