Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion

Ken Yu Lin, Dan Lu, Chien Fu Hung, Shiwen Peng, Lanqing Huang, Chunfa Jie, Francisco Murillo, Jesse Rowley, Ya Chea Tsai, Liangmei He, Dae Jin Kim, Elizabeth Jaffee, Drew Pardoll, T. C. Wu

Research output: Contribution to journalArticle

57 Scopus citations

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 α4β1 integrin. Site-directed mutagenesis of VCAM-1 at amino acid residues required for interaction with α4β1 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.

Original languageEnglish (US)
Pages (from-to)1832-1841
Number of pages10
JournalCancer research
Volume67
Issue number4
DOIs
StatePublished - Feb 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lin, K. Y., Lu, D., Hung, C. F., Peng, S., Huang, L., Jie, C., Murillo, F., Rowley, J., Tsai, Y. C., He, L., Kim, D. J., Jaffee, E., Pardoll, D., & Wu, T. C. (2007). Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion. Cancer research, 67(4), 1832-1841. https://doi.org/10.1158/0008-5472.CAN-06-3014