CD8+ T-cell responses against hemoglobin-beta prevent solid tumor growth.
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-beta (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.
Komita
Hideo
H
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Zhao
Xi
X
Taylor
Jennifer L
JL
Sparvero
Louis J
LJ
Amoscato
Andrew A
AA
Alber
Sean
S
Watkins
Simon C
SC
Pardee
Angela D
AD
Wesa
Amy K
AK
Storkus
Walter J
WJ
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D005260:Female; D006454:Hemoglobins / Q000037:antagonists & inhibitors / Q000276:immunology*; D007111:Immunity, Cellular / Q000502:physiology*; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use; D014185:Transplantation, Isogeneic / Q000276:immunology; D047368:Tumor Burden / Q000276:immunology; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D006454:Hemoglobins; D010446:Peptide Fragments