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CD8⁺ T-Cell Responses against Hemoglobin-β Prevent Solid Tumor Growth

Departments of ¹ Dermatology, ² Surgery, ³ Pathology, ⁴ Cell Biology and Physiology, and ⁵ Immunology, University of Pittsburgh School of Medicine and ⁶ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Walter J. Storkus, Departments of Dermatology and Immunology, University of Pittsburgh School of Medicine, W1041.2 Biomedical Sciences Tower, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-648-9981; Fax: 412-383-5857; E-mail: storkuswj{at}upmc.edu.

Key Words: Interleukin-12 • Gene Therapy • Tumor • Hemoglobin-β • Pericyte

Bone marrow–derived dendritic cells engineered using recombinant adenovirus to secrete high levels of IL-12p70 dramatically inhibited the growth of established CMS4 sarcomas in BALB/c mice after intratumoral administration. An analysis of splenic CD8⁺ T cells in regressor mice revealed a strong, complex reactivity pattern against high-performance liquid chromatography (HPLC)–resolved peptides isolated by acid elution from single-cell suspensions of surgically resected CMS4 lesions. Mass spectrometry analyses defined two major overlapping peptide species that derive from the murine hemoglobin-β (HBB) protein within the most stimulatory HPLC fractions. Although cultured CMS4 tumor cells failed to express HBB mRNA based on reverse transcription-PCR analyses, prophylactic vaccination of BALB/c mice with vaccines containing HBB peptides promoted specific CD8⁺ T-cell responses that protected mice against a subsequent challenge with CMS4 or unrelated syngeneic (HBB^neg) tumors of divergent histology (sarcoma, carcinomas of the breast or colon). In situ imaging suggested that vaccines limit or destabilize tumor-associated vascular structures, potentially by promoting immunity against HBB+ vascular pericytes. Importantly, there were no untoward effects of vaccination with the HBB peptide on peripheral RBC numbers, RBC hemoglobin content, or vascular structures in the brain or eye. [Cancer Res 2008;68(19):8076–84]