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.