title: Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice.
abstract: We have recently shown that effective cytokine gene therapy of solid tumors in HLA-A2 transgenic (HHD) mice lacking murine MHC class I molecule expression results in the generation of HLA-A2-restricted CD8(+) T effector cells selectively recognizing tumor blood vessel-associated pericytes and/or vascular endothelial cells. Using an HHD model in which HLA-A2(neg) tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8(+) T cell repertoire, we now show that vaccines on the basis of tumor-associated blood vessel Ags (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2(neg)) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8(+) (but not CD4(+)) T cells, in a coordinate reduction of CD31(+) blood vessels in the tumor microenvironment, and in the "spreading" of CD8(+) T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or vascular endothelial cells flow-sorted from tumor tissue but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8(+), but not CD4(+), T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 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: Nina
authors.initials: N
authors.lastname: Chi
authors.forename: Devin B
authors.initials: DB
authors.lastname: Lowe
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001808:Blood Vessels / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000276:immunology*; D005805:Genes, MHC Class I; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology*; D020286:Pericytes / Q000276:immunology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1