Abstract
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 (alpha(4) integrin) can form heterodimers with both beta(1) (CD29) and beta(7) integrins, alpha(4)beta(7) 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.
Highlights
Recent clinical studies have shown that superior clinical efficacy may be obtained through adoptive transfer of tumor-reactive autologous T cells, whereas active vaccination protocols rely on intact immune reactivity in cancer-bearing hosts, which is oftenNote: Supplementary data for this article are available at Cancer Research Online.H
In our previous study with mice bearing intracranial M05 melanoma, we showed that adoptively transferred ovalbumin (OVA)-specific Tc1 cells were superior to Tc2 cells in trafficking into the intracranial tumor lesions and in mediating potent therapeutic responses [4]
We show for the first time that very late antigen (VLA)-4 (CD49d/CD29) is preferentially expressed on Tc1 cells, but not on Tc2 cells, and that this integrin plays a critical role in the effective traffic of therapeutic Tc1 cells into central nervous system (CNS) tumors
Summary
Recent clinical studies have shown that superior clinical efficacy may be obtained through adoptive transfer of tumor-reactive autologous T cells, whereas active vaccination protocols rely on intact immune reactivity in cancer-bearing hosts, which is oftenNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).H. In our previous study with mice bearing intracranial M05 melanoma, we showed that adoptively transferred ovalbumin (OVA)-specific Tc1 cells were superior to Tc2 cells in trafficking into the intracranial tumor lesions and in mediating potent therapeutic responses [4]. These observations are consistent with previous reports by others that Tc2 (versus Tc1) cells are poorly recruited into sites of inflammation caused by viral infection or autoimmunity [5, 6], which may reflect differential expression of integrins/ addressins and/or chemokine receptors by these T-cell populations. The P-selectin and E-selectin ligands and the chemokine receptors CXCR3 and CCR5, associated with trafficking into sites of inflammation, are preferentially expressed on type 1 compared with type 2 T cells [7]
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