Friday, March 27, 2015

Attenuated Toxoplasma gondii stimulates immunity to pancreatic cancer by manipulation of myeloid cell populations

2015 Mar 24. pii: canimm.0235.2014. [Epub ahead of print]
Suppressive myeloid cells represent a significant barrier to the generation of productive anti-tumor 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 Toxoplasma gondii vaccine strain CPS would trigger tumor-associated myeloid cells to generate therapeutic anti-tumor immune responses. CPS 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 CPS, increased expression of co-stimulatory molecules CD80 and CD86 and concomitantly boosted their production of IL-12. CPS treatment increased CD4+ and CD8+ T cell infiltration into the tumor microenvironment, activated tumor-resident T cells, and increased IFN-γ production by T cell populations. CPS treatment provided a significant therapeutic benefit in pancreatic tumor-bearing mice. This therapeutic benefit depended on IL-12 and IFN-γ production, MyD88 signaling, and CD8+ T cell populations. Although CD4+ T cells exhibited activated effector phenotypes and produced IFN-γ, CD4+ T cells as well as NK cells were not required for the therapeutic benefit. In addition, CD8+ T cells isolated from CPS treated tumor-bearing mice produced IFN-γ after re-exposure to pancreatic tumor antigen, suggesting this immunotherapeutic treatment stimulated tumor cell antigen-specific CD8+ T cell responses. This work highlights the potency and immunotherapeutic efficacy of CPS treatment and demonstrates the significance of targeting tumor-associated myeloid cells as a mechanism to stimulate more effective immunity to pancreatic cancer.
Copyright © 2015, American Association for Cancer Research.
[PubMed - as supplied by publisher]

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