Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion.
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.
Lin
Ken-Yu
KY
Department of Pathology, Institute of Genetic Medicine, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA.
Lu
Dan
D
Hung
Chien-Fu
CF
Peng
Shiwen
S
Huang
Lanqing
L
Jie
Chunfa
C
Murillo
Francisco
F
Rowley
Jesse
J
Tsai
Ya-Chea
YC
He
Liangmei
L
Kim
Dae-Jin
DJ
Jaffee
Elizabeth
E
Pardoll
Drew
D
Wu
T-C
TC
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*
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