Regression of Established Mouse Leukemia by GM-CSF-Transduced Tumor Vaccine: Implications for Cytotoxic T Lymphocyte Responses and Tumor Burdens

Abstract

This study investigated the therapeutic effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on a mouse leukemia model. By using a retroviral vector, mouse GM-CSF cDNA was transduced into a highly tumorigenic T leukemia cell line, RL♂ 1. Injection of GM-CSF-secreting RL♂ 1 cells into syngeneic BALB/c mice elicited protective immunity in the animals, which could regress preestablished tumors introduced either by a subcutaneous or in an intravenous route. However, the therapeutic effects were less prominent in the mice inoculated with a large tumor load or in mice treated later. Winn tests further demonstrated that the splenocytes from the late-treated group conferred poorer protective effects in terms of reducing the growth of parental RL♂ 1 cells in naive mice than the splenocytes from the early-treated group. Nonetheless, upon stimulation in vitro, the activity of tumor-specific cytotoxic T lymphocytes (CTL) was comparable in the splenocytes of both groups of mice. Histological analysis also indicated that the CD8⁺ T cells appeared as early as 3 days following vaccination at the vaccine sites and at the tumor sites in both groups of mice. Above observations implied that the T cells in the animals bearing large tumors appeared to be in a state of suppression or anergy. Systematic histological analyses for 2 weeks provided further insight into various infiltrates at the vaccine sites and at the tumor sites in response to the inoculation of GM-CSF-secreting tumor vaccine.

Overview summary

As generally accepted, CD8⁺ T lymphocytes are an important effector involved in the GM-CSF-induced antitumor immunity. In this study, we have presented evidence that a tumor vaccine engineered to secrete GM-CSF exerted therapeutic effects on small tumor burdens, but not on large ones. Nonetheless, the CTLs were elicited in vivo regardless of whether the tumor vaccine was administered early or late and the levels and distribution were similar. The CTLs were active in vitro (in cytotoxicity assays) but less so in vivo (in the Winn test) in mice immunized at the later time points. Thus, our results imply that the antitumor immunity elicited by tumor vaccines could be down-modulated by large tumor burdens.