Enhanced therapeutic efficacy of tumor RNA-pulsed dendritic cells after genetic modification with lymphotactin

Hum Gene Ther. 1999 May 1;10(7):1151-61. doi: 10.1089/10430349950018148.

Abstract

Pulsing dendritic cells (DCs) with tumor cell-derived mRNA is regarded as an attractive alternative in the development of DC-based tumor vaccines. Our aim is to improve the therapeutic efficacy of DC-based tumor RNA vaccines by augmenting the preferential chemotaxis of DCs to T cells. Mouse bone marrow-derived DCs were genetically modified with lymphotactin (Lptn) by adenovirus vector, which conferred on DCs preferential chemotaxis to CD4+ and CD8+ T cells (Cao et al., 1998). Lptn gene-modified DCs (Lptn-DCs) were pulsed with tumor mRNA and used for vaccination in the tumor models of 3LL lung carcinoma and B16 melanoma. In both tumor models, immunization with 4 X 10(4) tumor RNA-pulsed Lptn-DCs induced more potent CTL activity, compared with their counterparts, specifically against tumor cells and Mut1 or tyrosinase-related protein 2 (TRP-2) peptide-pulsed RMA-S cells, and rendered the immunized mice resistant to tumor challenge much more effectively. CD8+ T cells were necessary and sufficient to generate the protection of Lptn-DC-based RNA tumor vaccines, and CD4+ T cells were required for the induction of tumor rejection. In the preestablished 3LL and B16 tumor models, vaccination with DC-based or LacZ-DC-based tumor RNA vaccines (2 X 10(5) cells) could reduce pulmonary metastasis and extend survival of tumor-bearing mice, but was less effective than the Lptn-DC counterpart (with 60-80% mice surviving). When the immunizing dose was decreased to 4 X 10(4) cells, Lptn-DC-based tumor vaccines rather than their counterparts were still significantly effective. Our studies provide a potential strategy to improve the efficacy of DC-based vaccines, and a new approach to immunological intervention by chemokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Bone Marrow Cells / immunology
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use*
  • Chemokines, C*
  • Dendritic Cells / immunology*
  • Genetic Vectors
  • Humans
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Lymphokines / genetics*
  • Melanoma, Experimental / secondary
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Neoplasm / genetics*
  • Sialoglycoproteins / genetics*
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Cancer Vaccines
  • Chemokines, C
  • Lymphokines
  • RNA, Messenger
  • RNA, Neoplasm
  • Sialoglycoproteins
  • XCL1 protein, human
  • Xcl1 protein, mouse
  • lymphotactin