This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Sasaki, K. Articles by Okada, H. Search for Related Content PubMed PubMed Citation Articles by Sasaki, K. Articles by Okada, H.

Preferential Expression of Very Late Antigen-4 on Type 1 CTL Cells Plays a Critical Role in Trafficking into Central Nervous System Tumors

Departments of ¹ Dermatology and Immunology and ² Neurological Surgery, University of Pittsburgh School of Medicine; ³ Biostatistics Department, University of Pittsburgh Graduate School of Public Health; ⁴ Brain Tumor Program and ⁵ Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁶ Laboratory of Tumor Immunology, Division of Oncology, Geneva University Hospital, Geneva, Switzerland

Requests for reprints: Hideho Okada, G12a Research Pavilion of the Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-1111; Fax: 412-623-4747; E-mail: okadah{at}upmc.edu.

We have previously shown preferential tumor-homing and therapeutic efficacy of adoptively transferred type 1 CTL (Tc1) when compared with type 2 CTL (Tc2) in mice bearing intracranial ovalbumin-transfected melanoma (M05). Further characterizing the expression of a panel of homing receptors on Tc1 and Tc2 cells, we found that very late antigen (VLA)-4 (a heterodimer of CD49d and CD29), but none of other receptors evaluated, was expressed at significantly higher levels on Tc1 cells than on Tc2 cells. Although CD49d (₄ integrin) can form heterodimers with both ß₁ (CD29) and ß₇ integrins, ₄ß₇ complexes were not expressed by either Tc1 or Tc2 cells, suggesting that CD49d is solely expressed in VLA-4 complexes. VLA-4 expression on Tc2 cells was down-regulated in an interleukin (IL)-4 dose-dependent manner but not by other type 2 cytokines, such as IL-10 and IL-13, suggesting that IL-4 uniquely down-regulates VLA-4 expression on these cells. In accordance with the differential expression of VLA-4 on Tc1 versus Tc2 cells, Tc1 cells alone were competent to adhere to plate-bound VCAM-1-Ig fusion protein. Finally, the efficient trafficking of Tc1 cells into intracranial M05 lesions in vivo was efficiently blocked by administration of monoclonal antibodies against CD49d or VCAM-1 or small interfering RNA–mediated silencing of CD49d on Tc1 cells. Collectively, these data support the critical role of VLA-4 in the effective intracranial tumor homing of adoptive-transferred, antigen-specific Tc1 cells and suggest that more effective vaccine and/or ex vivo T-cell activation regimens may be developed by promoting the generation of VLA-4⁺ antitumor Tc1 cells. [Cancer Res 2007;67(13):6451–8]

This article has been cited by other articles:

				R. Ueda, M. Fujita, X. Zhu, K. Sasaki, E. R. Kastenhuber, G. Kohanbash, H. A. McDonald, J. Harper, S. Lonning, and H. Okada Systemic Inhibition of Transforming Growth Factor-{beta} in Glioma-Bearing Mice Improves the Therapeutic Efficacy of Glioma-Associated Antigen Peptide Vaccines Clin. Cancer Res., November 1, 2009; 15(21): 6551 - 6559. [Abstract] [Full Text] [PDF]

				N. O. Deakin, M. D. Bass, S. Warwood, J. Schoelermann, Z. Mostafavi-Pour, D. Knight, C. Ballestrem, and M. J. Humphries An integrin-{alpha}4-14-3-3{zeta}-paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration J. Cell Sci., May 15, 2009; 122(10): 1654 - 1664. [Abstract] [Full Text] [PDF]

				M. Fujita, X. Zhu, R. Ueda, K. Sasaki, G. Kohanbash, E. R. Kastenhuber, H. A. McDonald, G. A. Gibson, S. C. Watkins, R. Muthuswamy, et al. Effective Immunotherapy against Murine Gliomas Using Type 1 Polarizing Dendritic Cells--Significant Roles of CXCL10 Cancer Res., February 15, 2009; 69(4): 1587 - 1595. [Abstract] [Full Text] [PDF]

				E. T. Clambey, J. White, J. W. Kappler, and P. Marrack Identification of two major types of age-associated CD8 clonal expansions with highly divergent properties PNAS, September 2, 2008; 105(35): 12997 - 13002. [Abstract] [Full Text] [PDF]

				K. Sasaki, X. Zhao, A. D. Pardee, R. Ueda, M. Fujita, S. Sehra, M. H. Kaplan, L. P. Kane, H. Okada, and W. J. Storkus Stat6 Signaling Suppresses VLA-4 Expression by CD8+ T Cells and Limits Their Ability to Infiltrate Tumor Lesions In Vivo J. Immunol., July 1, 2008; 181(1): 104 - 108. [Abstract] [Full Text] [PDF]

				M. Fujita, X. Zhu, K. Sasaki, R. Ueda, K. L. Low, I. F. Pollack, and H. Okada Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma J. Immunol., February 15, 2008; 180(4): 2089 - 2098. [Abstract] [Full Text] [PDF]