This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, J. A. Articles by Shu, S. Search for Related Content PubMed PubMed Citation Articles by Kim, J. A. Articles by Shu, S.

Divergent Effects of 4-1BB Antibodies on Antitumor Immunity and on Tumor-reactive T-Cell Generation¹

Department of General Surgery and Center for Surgery Research, Division of Surgery, Cleveland Clinic Foundation, Cleveland, Ohio 44195 [J. A. K., K. C., K. R., J. K., S. S.], and Department of Surgery, Metro Health Medical Center, Cleveland, Ohio 44109 [B. J. A.]

4-1BB is an inducible receptor-like protein expressed rapidly by both CD4 and CD8 T-cells after activation. 4-1BB cross-linking, either by binding to 4-1BBL or by antibody ligation, delivers a costimulatory signal to enhance T-cell activation and proliferation. Previous studies have demonstrated that the administration of 4-1BB monoclonal antibodies (mAbs) induces antitumor immune responses. In the current study using several murine tumors, we examined the systemic effects of 4-1BB mAb on the growth of s.c., intracranial (i.c.), and pulmonary metastases. In addition, the effects of 4-1BB mAb on the generation of antitumor effector T cells were examined. Treatment of 3-day i.c. MCA 205 sarcoma and GL261 glioma with the antibody resulted in prolongation of survival and cure of disease in some mice, whereas only minimal therapeutic effects were observed in established s.c. and pulmonary tumors. No antitumor effects against the poorly immunogenic B16/D5 melanoma were observed. Interestingly, successful treatment of i.c. tumors induced concomitant regression of s.c. tumors. Experiments using severe combined immunodeficient mice and mice depleted of either CD4 or CD8 T cells demonstrated T-cell dependence of the antitumor effects. For generation of effector T cells in the tumor-draining lymph nodes (LNs), administration of 4-1BB mAb had adverse effects, despite the apparent hypertrophy of the LNs. During in vitro activation of tumor-draining LN T cells with anti-CD3 and interleukin 2, the 4-1BB mAb augmented proliferation, resulting in an increase in CD8 T cells. However, they were less therapeutic than not treated LN cells. In adoptive immunotherapy, the coadministration of 4-1BB mAb enhanced the therapeutic efficacy. These results thus demonstrate the limits and potential advantages of 4-1BB antibody interactions with antitumor T cells in vivo and in vitro and suggest that therapeutic interactions of the antibody may be used in a variety of immunotherapeutic approaches.

This article has been cited by other articles:

				Y. H. Kim, B. K. Choi, K. H. Kim, S. W. Kang, and B. S. Kwon Combination Therapy with Cisplatin and Anti-4-1BB: Synergistic Anticancer Effects and Amelioration of Cisplatin-Induced Nephrotoxicity Cancer Res., September 15, 2008; 68(18): 7264 - 7269. [Abstract] [Full Text] [PDF]

				K. H. Yi, H. Nechushtan, W. J. Bowers, G. R. Walker, Y. Zhang, D. G. Pham, E. R. Podack, H. J. Federoff, K. A. Tolba, and J. D. Rosenblatt Adoptively Transferred Tumor-Specific T Cells Stimulated Ex vivo Using Herpes Simplex Virus Amplicons Encoding 4-1BBL Persist in the Host and Show Antitumor Activity In vivo Cancer Res., October 15, 2007; 67(20): 10027 - 10037. [Abstract] [Full Text] [PDF]

				B. K. Choi, Y. H. Kim, W. J. Kang, S. K. Lee, K. H. Kim, S. M. Shin, W. M. Yokoyama, T. Y. Kim, and B. S. Kwon Mechanisms Involved in Synergistic Anticancer Immunity of Anti-4-1BB and Anti-CD4 Therapy Cancer Res., September 15, 2007; 67(18): 8891 - 8899. [Abstract] [Full Text] [PDF]

				E. Ko, W. Luo, L. Peng, X. Wang, and S. Ferrone Mouse Dendritic-Endothelial Cell Hybrids and 4-1BB Costimulation Elicit Antitumor Effects Mediated by Broad Antiangiogenic Immunity Cancer Res., August 15, 2007; 67(16): 7875 - 7884. [Abstract] [Full Text] [PDF]

				S. Fuse, S. Bellfy, H. Yagita, and E. J. Usherwood CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand J. Immunol., April 15, 2007; 178(8): 5227 - 5236. [Abstract] [Full Text] [PDF]

				S.-C. Lee, S.-A. Ju, H.-N. Pack, S.-K. Heo, J.-H. Suh, S.-M. Park, B.-K. Choi, B. S. Kwon, and B. S. Kim 4-1BB (CD137) Is Required for Rapid Clearance of Listeria monocytogenes Infection Infect. Immun., August 1, 2005; 73(8): 5144 - 5151. [Abstract] [Full Text] [PDF]

				O. Murillo, A. Arina, I. Tirapu, C. Alfaro, G. Mazzolini, B. Palencia, A. L.-D. De Cerio, J. Prieto, M. Bendandi, and I. Melero Potentiation of Therapeutic Immune Responses against Malignancies with Monoclonal Antibodies Clin. Cancer Res., November 15, 2003; 9(15): 5454 - 5464. [Abstract] [Full Text] [PDF]

				Q. Li, A. Carr, F. Ito, S. Teitz-Tennenbaum, and A. E. Chang Polarization Effects of 4-1BB during CD28 Costimulation in Generating Tumor-reactive T Cells for Cancer Immunotherapy Cancer Res., May 15, 2003; 63(10): 2546 - 2552. [Abstract] [Full Text] [PDF]

				D. Laderach, M. Movassagh, A. Johnson, R. S. Mittler, and A. Galy 4-1BB co-stimulation enhances human CD8+ T cell priming by augmenting the proliferation and survival of effector CD8+ T cells Int. Immunol., October 1, 2002; 14(10): 1155 - 1167. [Abstract] [Full Text] [PDF]

				R. A. Wilcox, D. B. Flies, H. Wang, K. Tamada, A. J. Johnson, L. R. Pease, M. Rodriguez, Y. Guo, and L. Chen Impaired Infiltration of Tumor-specific Cytolytic T Cells in the Absence of Interferon-{gamma} despite Their Normal Maturation in Lymphoid Organs during CD137 Monoclonal Antibody Therapy Cancer Res., August 1, 2002; 62(15): 4413 - 4418. [Abstract] [Full Text] [PDF]

				K. F. May Jr., L. Chen, P. Zheng, and Y. Liu Anti-4-1BB Monoclonal Antibody Enhances Rejection of Large Tumor Burden by Promoting Survival but not Clonal Expansion of Tumor-specific CD8+ T Cells Cancer Res., June 1, 2002; 62(12): 3459 - 3465. [Abstract] [Full Text] [PDF]

				A. L. Tutt, L. O'Brien, A. Hussain, G. R. Crowther, R. R. French, and M. J. Glennie T Cell Immunity to Lymphoma Following Treatment with Anti-CD40 Monoclonal Antibody J. Immunol., March 15, 2002; 168(6): 2720 - 2728. [Abstract] [Full Text] [PDF]

				J. Kjaergaard, L. Peng, P. A. Cohen, J. A. Drazba, A. D. Weinberg, and S. Shu Augmentation Versus Inhibition: Effects of Conjunctional OX-40 Receptor Monoclonal Antibody and IL-2 Treatment on Adoptive Immunotherapy of Advanced Tumor J. Immunol., December 1, 2001; 167(11): 6669 - 6677. [Abstract] [Full Text] [PDF]