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Adoptive Transfer of Type 1 CTL Mediates Effective Anti–Central Nervous System Tumor Response: Critical Roles of IFN-Inducible Protein-10

Departments of ¹ Neurological Surgery, ² Surgery, ³ Dermatology and Immunology; and ⁴ Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

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.

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- cDNA (DC-IFN-) would enhance the tumor-homing and antitumor effectiveness of adoptively transferred Tc1 via induction of an IFN--inducible protein 10 (IP-10). In vitro, DC-IFN- 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- remarkably enhanced the tumor homing, therapeutic efficacy, and in situ IFN- 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. (Cancer Res 2006; 66(8): 4478-87)

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