Abstract
The development of effective immunotherapeutic strategies for central nervous system (CNS) tumors requires a firm understanding of factors regulating the trafficking of tumor antigen-specific CTLs into CNS tumor lesions. Using C57BL/6 mice bearing intracranial (i.c.) ovalbumin-transfected melanoma (M05), we evaluated the efficacy and tumor homing of i.v. transferred type 1 or 2 CTLs (Tc1 or Tc2, respectively) prepared from ovalbumin-specific T-cell receptor-transgenic OT-1 mice. We also tested our hypothesis that intratumoral (i.t.) delivery of dendritic cells that had been transduced with IFN-alpha cDNA (DC-IFN-alpha) would enhance the tumor-homing and antitumor effectiveness of adoptively transferred Tc1 via induction of an IFN-gamma-inducible protein 10 (IP-10). In vitro, DC-IFN-alpha induced IP-10 production by M05 and enhanced the cytolytic activity of Tc1. In vivo, i.v. transferred Tc1 trafficked efficiently into i.c. M05 and mediated antitumor responses more effectively than Tc2, and their effect was IP-10 dependent. I.t. injections of DC-IFN-alpha remarkably enhanced the tumor homing, therapeutic efficacy, and in situ IFN-gamma production of i.v. delivered Tc1, resulting in the long-term survival and persistence of systemic ovalbumin-specific immunity. These data suggest that Tc1-based adoptive transfer therapy may represent an effective modality for CNS tumors, particularly when combined with strategies that promote a type 1 polarized tumor microenvironment.
Highlights
We have recently identified glioma-associated antigen–derived CTL epitopes [1, 2] and developed glioma vaccine clinical trials for patients with glioma [3]
Tc1 cells expressed a higher level of CXCR3, a receptor for inducible protein 10 (IP-10) [15, 16], than Tc2, suggesting that Tc1 expressed a favorable phenotype toward potential migration to the inflammatory site in response to IP-10 (Supplementary Fig. S1)
We tested the ability of M05 to produce IP-10 under various culture conditions, including responses to IFN-a or IFN-g and to dendritic cells
Summary
We have recently identified glioma-associated antigen–derived CTL epitopes [1, 2] and developed glioma vaccine clinical trials for patients with glioma [3]. Active immunizations with glioma-associated antigen vaccines require the residual antitumor immune competence of the host, recent studies suggest that greater clinical efficacy may be obtained through the adoptive transfer of tumor-reactive, ex vivo– activated autologous T lymphocytes, when combined with nonmyeloablative but lymphodepleting chemotherapeutic. Doi:10.1158/0008-5472.CAN-05-3825 regimens [5, 6] This strategy may be suitable for patients with malignant gliomas because the clinical use of chemotherapeutic agents is rapidly becoming standard of care in these patients [7, 8]
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