title: Intratumoral IL-12 gene therapy results in the crosspriming of Tc1 cells reactive against tumor-associated stromal antigens.
abstract: HLA-A2 transgenic mice bearing established HLA-A2(neg) B16 melanomas were effectively treated by intratumoral (i.t.) injection of syngeneic dendritic cells (DCs) transduced to express high levels of interleukin (IL)-12, resulting in CD8(+) T cell-dependent antitumor protection. In this model, HLA-A2-restricted CD8(+) T cells do not directly recognize tumor cells and therapeutic benefit was associated with the crosspriming of HLA-A2-restricted type-1 CD8(+) T cells reactive against antigens expressed by stromal cells [i.e., pericytes and vascular endothelial cells (VEC)]. IL-12 gene therapy-induced CD8(+) T cells directly recognized HLA-A2(+) pericytes and VEC flow-sorted from B16 tumor lesions based on interferon (IFN)-γ secretion and translocation of the lytic granule-associated molecule CD107 to the T cell surface after coculture with these target cells. In contrast, these CD8(+) T effector cells failed to recognize pericytes/VEC isolated from the kidneys of tumor-bearing HHD mice. The tumor-associated stromal antigen (TASA)-derived peptides studied are evolutionarily conserved and could be recognized by CD8(+) T cells harvested from the blood of HLA-A2(+) normal donors or melanoma patients after in vitro stimulation. These TASA and their derivative peptides may prove useful in vaccine formulations against solid cancers, as well as, in the immune monitoring of HLA-A2(+) cancer patients receiving therapeutic interventions, such as IL-12 gene therapy.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
authors.forename: Hideo
authors.initials: H
authors.lastname: Komita
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kawabe
authors.forename: Nina
authors.initials: N
authors.lastname: Chi
authors.forename: Laima
authors.initials: L
authors.lastname: Spokas
authors.forename: Devin B
authors.initials: DB
authors.lastname: Lowe
authors.forename: Christina
authors.initials: C
authors.lastname: Goldbach
authors.forename: Sean
authors.initials: S
authors.lastname: Alber
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018664:Interleukin-12