title: Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion.
abstract: Immune escape is an important reason why the immune system cannot control tumor growth, but how escape variants emerge during immunotherapy remains poorly understood. Here, we identify a new mechanism of tumor immune escape using an in vivo selection strategy. We generated a highly immune-resistant cancer cell line (P3) by subjecting a susceptible cancer cell line (P0/TC-1) to multiple rounds of in vivo immune selection. Microarray analysis of P0 and P3 revealed that vascular cell adhesion molecule-1 (VCAM-1) is up-regulated in the P3-resistant variant. Retroviral transfer of VCAM-1 into P0 significantly increased its resistance against a vaccine-induced immune response. Analysis of tumors showed a dramatic decrease in the number of tumor-infiltrating cluster of differentiation 8(+) (CD8(+)) T cells in the tumors expressing VCAM-1. In vitro transwell migration assays showed that VCAM-1 can promote the migration of CD8(+) T cells through its interaction with the alpha(4)beta(1) integrin. Site-directed mutagenesis of VCAM-1 at amino acid residues required for interaction with alpha(4)beta(1) integrin completely abolished the immune resistance conferred by VCAM-1 in vivo. Surface staining showed that most renal cell carcinomas (RCC) express VCAM-1, whereas an RCC that responded to vaccination was VCAM-1 negative. These data provide evidence that tumor expression of VCAM-1 represents a new mechanism of immune evasion and has important implications for the development of immunotherapy for human RCC.
authors.affiliation: Department of Pathology, Institute of Genetic Medicine, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Ken-Yu
authors.initials: KY
authors.lastname: Lin
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.forename: Lanqing
authors.initials: L
authors.lastname: Huang
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.forename: Francisco
authors.initials: F
authors.lastname: Murillo
authors.forename: Jesse
authors.initials: J
authors.lastname: Rowley
authors.forename: Ya-Chea
authors.initials: YC
authors.lastname: Tsai
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: Dae-Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jaffee
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D015536:Down-Regulation; D007167:Immunotherapy / Q000379:methods; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000276:immunology*
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D039041:Integrin alpha4beta1; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D019010:Vascular Cell Adhesion Molecule-1; C059731:oncogene protein E7, Human papillomavirus type 16