| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
,
*
Department of Veterans Affairs Medical Center, Iowa City, IA 52246;
Department of Internal Medicine and the University of Iowa Holden Cancer Center, University of Iowa College of Medicine, Iowa City, IA 52242;
Coley Pharmaceutical Group, Wellesley, MA 02481; and
Loeb Health Research Institute, Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada
Immune stimulatory oligodeoxynucleotides (ODN) with unmethylated CpG motifs are potent inducers of both innate and adaptive immunity. It initially appeared that a single type of optimal CpG motif would work in all applications. We now report that specific motifs of CpG ODN can vary dramatically in their ability to induce individual immune effects and that these differences impact on their antitumor activity in different tumor models. In particular, a distinct type of CpG motif, which has a chimeric backbone in combination with poly(G) tails, is a potent inducer of NK lytic activity but has little effect on cytokine secretion or B cell proliferation. One such NK-optimized CpG ODN (1585) can induce regression of established melanomas in mice. Surprisingly, no such therapeutic effects were seen with CpG ODN optimized for activation of B cells and Th1-like cytokine expression (ODN 1826). The therapeutic effects of CpG 1585 in melanoma required the presence of NK but not T or B cells and were not associated with the induction of a tumor-specific memory response. In contrast, CpG 1826, but not CpG 1585, was effective at inducing regression of the EL4 murine lymphoma; this rejection was associated with the induction of a memory response and although NK cells were necessary, they were not sufficient. These results demonstrate that selection of optimal CpG ODN for cancer immunotherapy depends upon a careful analysis of the cellular specificities of various CpG motifs and an understanding of the cellular mechanisms responsible for the antitumor activity in a particular tumor.
This article has been cited by other articles:
|
|
 |
|
  A. M. Avalos, E. Latz, B. Mousseau, S. R. Christensen, M. J. Shlomchik, F. Lund, and A. Marshak-Rothstein Differential Cytokine Production and Bystander Activation of Autoreactive B Cells in Response to CpG-A and CpG-B Oligonucleotides J. Immunol., November 15, 2009; 183(10): 6262 - 6268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wakita, K. Chamoto, T. Ohkuri, Y. Narita, S. Ashino, K. Sumida, H. Nishikawa, H. Shiku, Y. Togashi, H. Kitamura, et al. IFN-{gamma}-dependent type 1 immunity is crucial for immunosurveillance against squamous cell carcinoma in a novel mouse carcinogenesis model Carcinogenesis, August 1, 2009; 30(8): 1408 - 1415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Thaxton, R. Romero, and S. Sharma TLR9 Activation Coupled to IL-10 Deficiency Induces Adverse Pregnancy Outcomes J. Immunol., July 15, 2009; 183(2): 1144 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Bhan, G. Trujillo, K. Lyn-Kew, M. W. Newstead, X. Zeng, C. M. Hogaboam, A. M. Krieg, and T. J. Standiford Toll-Like Receptor 9 Regulates the Lung Macrophage Phenotype and Host Immunity in Murine Pneumonia Caused by Legionella pneumophila Infect. Immun., July 1, 2008; 76(7): 2895 - 2904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Anderson, G. J. Cianciolo, M. N. Kennedy, and S. V. Pizzo {alpha}2-Macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism J. Leukoc. Biol., February 1, 2008; 83(2): 381 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Kochenderfer and R. E. Gress A Comparison and Critical Analysis of Preclinical Anticancer Vaccination Strategies Experimental Biology and Medicine, October 1, 2007; 232(9): 1130 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Li, W. Song, D. K. Czerwinski, B. Varghese, S. Uematsu, S. Akira, A. M. Krieg, and R. Levy Lymphoma Immunotherapy with CpG Oligodeoxynucleotides Requires TLR9 Either in the Host or in the Tumor Itself J. Immunol., August 15, 2007; 179(4): 2493 - 2500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Kochenderfer, J. L. Simpson, C. D. Chien, and R. E. Gress Vaccination regimens incorporating CpG-containing oligodeoxynucleotides and IL-2 generate antigen-specific antitumor immunity from T-cell populations undergoing homeostatic peripheral expansion after BMT Blood, July 1, 2007; 110(1): 450 - 460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Durakovic, V. Radojcic, M. Skarica, K. B. Bezak, J. D. Powell, E. J. Fuchs, and L. Luznik Factors governing the activation of adoptively transferred donor T cells infused after allogeneic bone marrow transplantation in the mouse Blood, May 15, 2007; 109(10): 4564 - 4574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bourquin, L. Schmidt, V. Hornung, C. Wurzenberger, D. Anz, N. Sandholzer, S. Schreiber, A. Voelkl, G. Hartmann, and S. Endres Immunostimulatory RNA oligonucleotides trigger an antigen-specific cytotoxic T-cell and IgG2a response Blood, April 1, 2007; 109(7): 2953 - 2960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Flores, K. A. Diggs, L. M. Tait, and P. A. Morel IFN-{gamma} Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells J. Immunol., January 1, 2007; 178(1): 211 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Kochenderfer, C. D. Chien, J. L. Simpson, and R. E. Gress Synergism between CpG-Containing Oligodeoxynucleotides and IL-2 Causes Dramatic Enhancement of Vaccine-Elicited CD8+ T Cell Responses J. Immunol., December 15, 2006; 177(12): 8860 - 8873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Kozak, S. Wrotek, and A. Kozak Pyrogenicity of CpG-DNA in mice: role of interleukin-6, cyclooxygenases, and nuclear factor-{kappa}B Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R871 - R880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Chaperot, A. Blum, O. Manches, G. Lui, J. Angel, J.-P. Molens, and J. Plumas Virus or TLR Agonists Induce TRAIL-Mediated Cytotoxic Activity of Plasmacytoid Dendritic Cells J. Immunol., January 1, 2006; 176(1): 248 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. N. Buhtoiarov, H. D. Lum, G. Berke, P. M. Sondel, and A. L. Rakhmilevich Synergistic Activation of Macrophages via CD40 and TLR9 Results in T Cell Independent Antitumor Effects J. Immunol., January 1, 2006; 176(1): 309 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gregoire, A. S. Bergot, C. Feraudet, C. Carnaud, P. Aucouturier, and M. B. Rosset The Murine B Cell Repertoire Is Severely Selected against Endogenous Cellular Prion Protein J. Immunol., November 15, 2005; 175(10): 6443 - 6449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. D. Reid, K. She, L. Terrett, M. R. Food, J. D. Trudeau, and K. R. Schultz CpG stimulation of precursor B-lineage acute lymphoblastic leukemia induces a distinct change in costimulatory molecule expression and shifts allogeneic T cells toward a Th1 response Blood, May 1, 2005; 105(9): 3641 - 3647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Poon, J. T. Safrit, H. McClure, C. Kitchen, J. F. Hsu, V. Gudeman, C. Petropoulos, T. Wrin, I. S. Y. Chen, and K. Grovit-Ferbas Induction of Humoral Immune Responses following Vaccination with Envelope-Containing, Formaldehyde-Treated, Thermally Inactivated Human Immunodeficiency Virus Type 1 J. Virol., April 15, 2005; 79(8): 4927 - 4935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Brummel and P. Lenert Activation of Marginal Zone B Cells from Lupus Mice with Type A(D) CpG-Oligodeoxynucleotides J. Immunol., February 15, 2005; 174(4): 2429 - 2434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Jahrsdorfer, L. Muhlenhoff, S. E. Blackwell, M. Wagner, H. Poeck, E. Hartmann, R. Jox, T. Giese, B. Emmerich, S. Endres, et al. B-Cell Lymphomas Differ in their Responsiveness to CpG Oligodeoxynucleotides Clin. Cancer Res., February 15, 2005; 11(4): 1490 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Mason, H. Ariga, R. Neal, D. Valdecanas, N. Hunter, A. M. Krieg, J. K. Whisnant, and L. Milas Targeting Toll-like Receptor 9 with CpG Oligodeoxynucleotides Enhances Tumor Response to Fractionated Radiotherapy Clin. Cancer Res., January 1, 2005; 11(1): 361 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Christiansen and A. K. Rajasekaran Biological impediments to monoclonal antibody-based cancer immunotherapy Mol. Cancer Ther., November 1, 2004; 3(11): 1493 - 1501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Deng, T. A. Moore, M. W. Newstead, X. Zeng, A. M. Krieg, and T. J. Standiford CpG Oligodeoxynucleotides Stimulate Protective Innate Immunity against Pulmonary Klebsiella Infection J. Immunol., October 15, 2004; 173(8): 5148 - 5155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Vollmer, R. D. Weeratna, M. Jurk, H. L. Davis, C. Schetter, M. Wullner, T. Wader, M. Liu, A. Kritzler, and A. M. Krieg Impact of modifications of heterocyclic bases in CpG dinucleotides on their immune-modulatory activity J. Leukoc. Biol., September 1, 2004; 76(3): 585 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. N. Wu, J. Lee, E. Raz, M. Corr, and D. A. Carson Necessity of Oligonucleotide Aggregation for Toll-like Receptor 9 Activation J. Biol. Chem., August 6, 2004; 279(32): 33071 - 33078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Benimetskaya, T. Wittenberger, C. A. Stein, H.-P. Hofmann, C. Weller, J. C. Lai, P. Miller, and V. Gekeler Changes in Gene Expression Induced by Phosphorothioate Oligodeoxynucleotides (Including G3139) in PC3 Prostate Carcinoma Cells Are Recapitulated at Least in Part by Treatment with Interferon-{beta} and -{gamma} Clin. Cancer Res., June 1, 2004; 10(11): 3678 - 3688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Rosset, C. Ballerini, S. Gregoire, P. Metharom, C. Carnaud, and P. Aucouturier Breaking Immune Tolerance to the Prion Protein Using Prion Protein Peptides Plus Oligodeoxynucleotide-CpG in Mice J. Immunol., May 1, 2004; 172(9): 5168 - 5174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Campbell, V. Bovenzi, and M. Szyf Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo Carcinogenesis, April 1, 2004; 25(4): 499 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-F. Chen, C.-W. Lin, Y.-P. Tsao, and S.-L. Chen Cytotoxic-T-Lymphocyte Human Papillomavirus Type 16 E5 Peptide with CpG-Oligodeoxynucleotide Can Eliminate Tumor Growth in C57BL/6 Mice J. Virol., February 1, 2004; 78(3): 1333 - 1343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Duramad, K. L. Fearon, J. H. Chan, H. Kanzler, J. D. Marshall, R. L. Coffman, and F. J. Barrat IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences Blood, December 15, 2003; 102(13): 4487 - 4492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schirmbeck, P. Riedl, R. Zurbriggen, S. Akira, and J. Reimann Antigenic Epitopes Fused to Cationic Peptide Bound to Oligonucleotides Facilitate Toll-Like Receptor 9-Dependent, but CD4+ T Cell Help-Independent, Priming of CD8+ T Cells J. Immunol., November 15, 2003; 171(10): 5198 - 5207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lundberg, P. Welander, X. Han, and E. Cantin Herpes Simplex Virus Type 1 DNA Is Immunostimulatory In Vitro and In Vivo J. Virol., October 15, 2003; 77(20): 11158 - 11169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lore, M. R. Betts, J. M. Brenchley, J. Kuruppu, S. Khojasteh, S. Perfetto, M. Roederer, R. A. Seder, and R. A. Koup Toll-Like Receptor Ligands Modulate Dendritic Cells to Augment Cytomegalovirus- and HIV-1-Specific T Cell Responses J. Immunol., October 15, 2003; 171(8): 4320 - 4328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Hartmann, B. Wollenberg, S. Rothenfusser, M. Wagner, D. Wellisch, B. Mack, T. Giese, O. Gires, S. Endres, and G. Hartmann Identification and Functional Analysis of Tumor-Infiltrating Plasmacytoid Dendritic Cells in Head and Neck Cancer Cancer Res., October 1, 2003; 63(19): 6478 - 6487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Beloeil, M. Tomkowiak, G. Angelov, T. Walzer, P. Dubois, and J. Marvel In Vivo Impact of CpG1826 Oligodeoxynucleotide on CD8 T Cell Primary Responses and Survival J. Immunol., September 15, 2003; 171(6): 2995 - 3002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. H. van Ojik, L. Bevaart, C. E. Dahle, A. Bakker, M. J. H. Jansen, M. J. van Vugt, J. G. J. van de Winkel, and G. J. Weiner CpG-A and B Oligodeoxynucleotides Enhance the Efficacy of Antibody Therapy by Activating Different Effector Cell Populations Cancer Res., September 1, 2003; 63(17): 5595 - 5600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Weigel, D. A. Rodeberg, A. M. Krieg, and B. R. Blazar CpG Oligodeoxynucleotides Potentiate the Antitumor Effects of Chemotherapy or Tumor Resection in an Orthotopic Murine Model of Rhabdomyosarcoma Clin. Cancer Res., August 1, 2003; 9(8): 3105 - 3114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Baines and E. Celis Immune-mediated Tumor Regression Induced by CpG-containing Oligodeoxynucleotides Clin. Cancer Res., July 1, 2003; 9(7): 2693 - 2700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hemmi, T. Kaisho, K. Takeda, and S. Akira The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets J. Immunol., March 15, 2003; 170(6): 3059 - 3064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Farman and D. J. Kornbrust Oligodeoxynucleotide Studies in Primates: Antisense and Immune Stimulatory Indications Toxicol Pathol, January 1, 2003; 31(1_suppl): 119 - 122. [Abstract] [PDF]
|
|
|
|
|
|
K. Heckelsmiller, K. Rall, S. Beck, A. Schlamp, J. Seiderer, B. Jahrsdorfer, A. Krug, S. Rothenfusser, S. Endres, and G. Hartmann Peritumoral CpG DNA Elicits a Coordinated Response of CD8 T Cells and Innate Effectors to Cure Established Tumors in a Murine Colon Carcinoma Model J. Immunol., October 1, 2002; 169(7): 3892 - 3899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Vicari, C. Chiodoni, C. Vaure, S. Ait-Yahia, C. Dercamp, F. Matsos, O. Reynard, C. Taverne, P. Merle, M. P. Colombo, et al. Reversal of Tumor-induced Dendritic Cell Paralysis by CpG Immunostimulatory Oligonucleotide and Anti-Interleukin 10 Receptor Antibody J. Exp. Med., August 19, 2002; 196(4): 541 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. Rhee, S. Mendez, J. A. Shah, C.-y. Wu, J. R. Kirman, T. N. Turon, D. F. Davey, H. Davis, D. M. Klinman, R. N. Coler, et al. Vaccination with Heat-killed Leishmania Antigen or Recombinant Leishmanial Protein and CpG Oligodeoxynucleotides Induces Long-Term Memory CD4+and CD8+T Cell Responses and Protection Against Leishmania major Infection J. Exp. Med., June 17, 2002; 195(12): 1565 - 1573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gursel, D. Verthelyi, I. Gursel, K. J. Ishii, and D. M. Klinman Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide J. Leukoc. Biol., May 1, 2002; 71(5): 813 - 820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Yu, E. R. Kandimalla, Q. Zhao, Y. Cong, and S. Agrawal Immunostimulatory properties of phosphorothioate CpG DNA containing both 3'-5'- and 2'-5'-internucleotide linkages Nucleic Acids Res., April 1, 2002; 30(7): 1613 - 1619. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
