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Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment.

Publication ,  Journal Article
Baird, JR; Fox, BA; Sanders, KL; Lizotte, PH; Cubillos-Ruiz, JR; Scarlett, UK; Rutkowski, MR; Conejo-Garcia, JR; Fiering, S; Bzik, DJ
Published in: Cancer Res
July 1, 2013

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.

Duke Scholars

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2013

Volume

73

Issue

13

Start / End Page

3842 / 3851

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tumor Microenvironment
  • Tumor Escape
  • Tumor Burden
  • Toxoplasma
  • Spleen
  • Protozoan Vaccines
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
 

Citation

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Baird, J. R., Fox, B. A., Sanders, K. L., Lizotte, P. H., Cubillos-Ruiz, J. R., Scarlett, U. K., … Bzik, D. J. (2013). Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment. Cancer Res, 73(13), 3842–3851. https://doi.org/10.1158/0008-5472.CAN-12-1974
Baird, Jason R., Barbara A. Fox, Kiah L. Sanders, Patrick H. Lizotte, Juan R. Cubillos-Ruiz, Uciane K. Scarlett, Melanie R. Rutkowski, Jose R. Conejo-Garcia, Steven Fiering, and David J. Bzik. “Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment.Cancer Res 73, no. 13 (July 1, 2013): 3842–51. https://doi.org/10.1158/0008-5472.CAN-12-1974.
Baird JR, Fox BA, Sanders KL, Lizotte PH, Cubillos-Ruiz JR, Scarlett UK, et al. Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment. Cancer Res. 2013 Jul 1;73(13):3842–51.
Baird, Jason R., et al. “Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment.Cancer Res, vol. 73, no. 13, July 2013, pp. 3842–51. Pubmed, doi:10.1158/0008-5472.CAN-12-1974.
Baird JR, Fox BA, Sanders KL, Lizotte PH, Cubillos-Ruiz JR, Scarlett UK, Rutkowski MR, Conejo-Garcia JR, Fiering S, Bzik DJ. Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment. Cancer Res. 2013 Jul 1;73(13):3842–3851.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2013

Volume

73

Issue

13

Start / End Page

3842 / 3851

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tumor Microenvironment
  • Tumor Escape
  • Tumor Burden
  • Toxoplasma
  • Spleen
  • Protozoan Vaccines
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation