Tumor suppressive efficacy through augmentation of tumor-infiltrating immune cells by intratumoral injection of chemokine-expressing adenoviral vector

Cancer Gene Ther. 2006 Apr;13(4):393-405. doi: 10.1038/sj.cgt.7700903.

Abstract

Our goal in the present study was to evaluate antitumor effects and frequency of tumor-infiltrating immune cells upon intratumoral injection of RGD fiber-mutant adenoviral vector (AdRGD) encoding the chemokines CCL17, CCL19, CCL20, CCL21, CCL22, CCL27, XCL1, and CX3CL1. Among eight kinds of chemokine-expressing AdRGDs, AdRGD-CCL19 injection most efficiently induced infiltration of T cells into established B16BL6 tumor parenchyma, whereas most of these T cells were perforin-negative in immunohistochemical analysis. Additionally, the growth of AdRGD-CCL19-injected tumors decreased only slightly as well as that of other tumors treated with each chemokine-expressing AdRGD, which indicated that accumulation of naive T cells in tumor tissue does not effectively damage the tumor cells. Tumor-bearing mice, in which B16BL6-specific T cells were elicited by dendritic cell-based immunization, demonstrated that intratumoral injection of AdRGD-CCL17, -CCL22, or -CCL27 could considerably suppress tumor growth and attract activated T cells. On the other hand, AdRGD-CCL19-injection in the immunized mice showed slight increase of tumor-infiltrating T cells compared to treatment using control vector. Collectively, although AdRGD-mediated chemokine gene transduction into established tumors would be very useful for augmentation of tumor-infiltrating immune cells, a combinational treatment that can systemically induce tumor-specific effector T cells is necessary for satisfactory antitumor efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Capsid Proteins / genetics
  • Cell Line, Tumor
  • Chemokines / biosynthesis*
  • Chemokines / genetics
  • Chemokines / immunology
  • Dendritic Cells / immunology
  • Female
  • Genetic Therapy
  • Genetic Vectors* / immunology
  • Lymphocyte Subsets / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Oligopeptides / genetics
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transduction, Genetic
  • gp100 Melanoma Antigen

Substances

  • Capsid Proteins
  • Chemokines
  • Membrane Glycoproteins
  • Oligopeptides
  • Pmel protein, mouse
  • gp100 Melanoma Antigen
  • arginyl-glycyl-aspartic acid