Reversing
tumor-associated immunosuppression seems necessary to stimulate effective therapeutic immunity against lethal epithelial
tumors. Here, we show this goal can be addressed using cps, an avirulent, nonreplicating
uracil auxotroph strain of the parasite Toxoplasma gondii (T. gondii), which preferentially invades immunosuppressive
CD11c(+) antigen-presenting cells in the ovarian
carcinoma microenvironment.
Tumor-associated CD11c(+) cells invaded by cps were converted to immunostimulatory phenotypes, which expressed increased levels of the
T-cell receptor costimulatory molecules CD80 and CD86. In response to cps treatment of the immunosuppressive ovarian
tumor environment, CD11c(+) cells regained the ability to efficiently cross-present
antigen and prime CD8(+) T-cell responses. Correspondingly, cps treatment markedly increased
tumor antigen-specific responses by CD8(+) T cells. Adoptive transfer experiments showed that these antitumor T-cell responses were effective in suppressing solid
tumor development. Indeed, intraperitoneal cps treatment triggered rejection of established ID8-VegfA
tumors, an aggressive xenograft model of ovarian
carcinoma, also conferring a survival benefit in a related aggressive model (ID8-Defb29/
Vegf-A). The therapeutic benefit of cps treatment relied on expression of
IL-12, but it was unexpectedly independent of MyD88 signaling as well as immune experience with T. gondii. Taken together, our results establish that cps preferentially invades
tumor-associated antigen-presenting cells and restores their ability to trigger potent antitumor CD8(+) T-cell responses. Immunochemotherapeutic applications of cps might be broadly useful to reawaken natural immunity in the highly immunosuppressive microenvironment of most solid
tumors.