Tumor-Induced Immunosuppression: A Barrier to Immunotherapy of Large Tumors by Cytokine-Secreting Tumor Vaccine

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 beta (TGF-beta) and interleukin 10 (IL-10), the potent immunosuppressive factors, was detected in the parental tumor cell line RL male 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- beta in the conditioned medium of RL male 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 male 1 cultured in a serum- free medium, in which the TGF-beta 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