Data from Attenuated <i>Toxoplasma gondii</i> Stimulates Immunity to Pancreatic Cancer by Manipulation of Myeloid Cell Populations

Abstract

<div>Abstract<p>Suppressive myeloid cells represent a significant barrier to the generation of productive antitumor immune responses to many solid tumors. Eliminating or reprogramming suppressive myeloid cells to abrogate tumor-associated immune suppression is a promising therapeutic approach. We asked whether treatment of established aggressive disseminated pancreatic cancer with the immunotherapeutic attenuated <i>Toxoplasma gondii</i> vaccine strain <i>CPS</i> would trigger tumor-associated myeloid cells to generate therapeutic antitumor immune responses. <i>CPS</i> treatment significantly decreased tumor-associated macrophages and markedly increased dendritic cell infiltration of the pancreatic tumor microenvironment. Tumor-resident macrophages and dendritic cells, particularly cells actively invaded by <i>CPS</i>, increased expression of costimulatory molecules CD80 and CD86 and concomitantly boosted their production of IL12. <i>CPS</i> treatment increased CD4<sup>+</sup> and CD8<sup>+</sup> T-cell infiltration into the tumor microenvironment, activated tumor-resident T cells, and increased IFNγ production by T-cell populations. <i>CPS</i> treatment provided a significant therapeutic benefit in pancreatic tumor-bearing mice. This therapeutic benefit depended on IL12 and IFNγ production, MyD88 signaling, and CD8<sup>+</sup> T-cell populations. Although CD4<sup>+</sup> T cells exhibited activated effector phenotypes and produced IFNγ, CD4<sup>+</sup> T cells as well as natural killer cells were not required for the therapeutic benefit. In addition, CD8<sup>+</sup> T cells isolated from <i>CPS</i>-treated tumor-bearing mice produced IFNγ after re-exposure to pancreatic tumor antigen, suggesting this immunotherapeutic treatment stimulated tumor cell antigen-specific CD8<sup>+</sup> T-cell responses. This work highlights the potency and immunotherapeutic efficacy of <i>CPS</i> treatment and demonstrates the significance of targeting tumor-associated myeloid cells as a mechanism to stimulate more effective immunity to pancreatic cancer. <i>Cancer Immunol Res; 3(8); 891–901. ©2015 AACR</i>.</p></div>