Tumor-induced immunosuppression: A barrier to immunotherapy of large tumors by cytokine-secreting tumor vaccine
Journal
Human Gene Therapy
Journal Volume
11
Journal Issue
5
Pages
681-692
Date Issued
2000
Author(s)
Abstract
An active immunotherapy strategy with cytokine-assisted tumor vaccine, although often effective for small tumor burdens, is much less so for large tumor burdens. This study examines how large tumors might suppress the T cell functions and escape from the immune responses elicited by a granulocyte- macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine. According to our results, the T cells isolated from the tumor-bearing mice treated late with the vaccine failed to confer protective activity on naive mice against a wild-type tumor challenge, unlike those isolated from the early-treated group. Nevertheless, the antitumor activity of the inactive T cells could be restored on in vitro stimulation. Expression of transforming growth factor β (TGF-β) and interleukin 10 (IL-10), the potent immunosuppressive factors, was detected in the parental tumor cell line RL♂ 1 (a murine T leukemia cell line), as well as in the tumor region, the levels of which correlated with tumor progression. An in vitro assay of T cell functions revealed that the TGF-β in the conditioned medium of RL♂ 1 cells mainly affected the activation, whereas the IL-10 affected the activation to a lesser extent, but significantly affected the cytolytic activity, of tumor- specific T cells. The immunosuppressive activity of IL-10 was also signified by the findings that administration of the conditioned medium of RL♂ 1 cultured in a serum-free medium, in which the TGF-β activity was then lost while the IL-10 activity still remained, or of recombinant IL-10 to the early-treated group of mice abrogated the known efficacy of tumor vaccine on the small tumors. These data suggested that the efficacy of cytokine- secreting tumor vaccine was blocked by the immunosuppressive factors secreted from the large tumors. The results have important implications for the clinical design of immunotherapeutic strategies for advanced cancer patients.
SDGs
Other Subjects
granulocyte macrophage colony stimulating factor; interleukin 10; transforming growth factor beta; tumor vaccine; animal experiment; animal model; animal tissue; antineoplastic activity; article; cancer immunotherapy; controlled study; cytotoxic T lymphocyte; immune deficiency; male; mouse; murine leukemia; nonhuman; tumor associated leukocyte; tumor escape; Animals; Cancer Vaccines; CD8-Positive T-Lymphocytes; Cell Division; Culture Media, Conditioned; Cytokines; Immunosuppression; Immunotherapy; Interleukin-10; Leukemia, Experimental; Male; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Recombinant Proteins; T-Lymphocytes; Transforming Growth Factor beta; Animalia; Murinae
Type
journal article