Adoptive transfer of type 1 CTL mediates effective anti-central nervous system tumor response: critical roles of IFN-inducible protein-10.
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.
Nishimura
Fumihiko
F
Department of Neurological Surgery, University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Dusak
Jill E
JE
Eguchi
Junichi
J
Zhu
Xinmei
X
Gambotto
Andrea
A
Storkus
Walter J
WJ
Okada
Hideho
H
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016898:Interferon-alpha; D010047:Ovalbumin