Regulatory balance between the immune response of tumor antigen-specific T-cell receptor gene-transduced CD8 T cells and the suppressive effects of tolerogenic dendritic cells.
Tumor immune responses, including some immunotherapy strategies, can fail because of a number of reasons, such as poor tumor cell immunogenicity or local suppressive cytokine release by dendritic cells (DC) at tumor sites. The retroviral transfer of T-cell receptor (TCR) genes encoding tumor-specific receptors into T cells is a fascinating approach to bypass antigen-presenting cells and allow T cells to directly recognize antigen. It also allows the generation and expansion of potent antitumor cytotoxic T lymphocytes with defined cancer antigen specificities more readily than naive T cells. However, interleukin-10 (IL-10)-exposed dendritic cells (IL-10-DC) have been labeled tolerogenic because of the suppressive effects they have on T cell responses. Whether TCR gene-transduced effector CD8(+) T cells can break through suppressive functions mediated by IL-10-DC is not known. In the current study, we demonstrate the role of IL-10 in modifying the function of DC that otherwise would activate potent TCR gene-transduced T cells against tumor antigens. TCR gene-transduced T cells maintained their cytolytic activity in the presence of DC exposed to low doses of IL-10 during maturation; however, they lost this activity in an antigen-specific manner when exposed to DC matured with high doses of IL-10.
Fujii
Shin-Ichiro
S
Research Unit for Cellular Immunotherapy, Research Center for Allergy and Immunology (RCAI), RIKEN, Yokohama, Kanagawa 230-0045, Japan. fujis@rcai.riken.jp
Nishimura
Michael I
MI
Lotze
Michael T
MT
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor