AttenuatedToxoplasma gondiiStimulates Immunity to Pancreatic Cancer by Manipulation of Myeloid Cell Populations

Abstract

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 Toxoplasma gondii vaccine strain CPS would trigger tumor-associated myeloid cells to generate therapeutic antitumor 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 IL12. CPS treatment increased CD4+ and CD8+ T-cell infiltration into the tumor microenvironment, activated tumor-resident T cells, and increased IFNγ production by T-cell populations. CPS treatment provided a significant therapeutic benefit in pancreatic tumor-bearing mice. This therapeutic benefit depended on IL12 and IFNγ production, MyD88 signaling, and CD8+ T-cell populations. Although CD4+ T cells exhibited activated effector phenotypes and produced IFNγ, 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 IFNγ 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.

Study the Possible Link Between Toxoplasmosis and Different Kinds of Cancer in Iraq

“…The authors concluded that CPS treatment provided a significant therapeutic benefit in pancreatic tumor-bearing mice via targeting tumor-associated myeloid cells as a mechanism to stimulate more effective immunity to pancreatic cancer. Although the results of this pioneer study are very interesting, unfortunately cannot be compared with the results of the current study and those of Yuan et al [29], Thomas et al [30], Vittecoq et al [31], and those of Cong et al [32] because the strain used in Sanders et al [34] study was experimentally immunotherapeutic attenuated Toxoplasma gondii vaccine while those in the present study and other studies were not attenuated and supposedly pathogenic strains. In contrast, T. gondii has the ability to manipulate host cell signaling pathways and processes by interfering with the gene expression profiles of the invaded cells [35] which in turn respond by initiating apoptotic response which reduces survival and proliferation of the parasites and makes the parasites susceptible to immune attack.…”

Attenuated Toxoplasma gondii therapy of disseminated pancreatic cancer generates long-lasting immunity to pancreatic cancer

“…7,8 CPS treatment of tumor-bearing mice promoted longlasting tumor-free survival in highly aggressive murine solid tumor models for ovarian cancer, for melanoma, and for pancreatic cancer. [9][10][11] This remarkably effective protection from the primary tumor is triggered and coordinated by CPS manipulation of tumor-associated myeloid cells, which leads to the elimination of tumor-associated immune suppression, thereby promoting the activation of significant antitumor immune responses. [9][10][11][12][13] CPS therapy strongly induced the production of IL-12 and IFNg, and stimulated tumor cell specific effector CD8 C T cell populations.…”

“…[9][10][11] This remarkably effective protection from the primary tumor is triggered and coordinated by CPS manipulation of tumor-associated myeloid cells, which leads to the elimination of tumor-associated immune suppression, thereby promoting the activation of significant antitumor immune responses. [9][10][11][12][13] CPS therapy strongly induced the production of IL-12 and IFNg, and stimulated tumor cell specific effector CD8 C T cell populations. Moreover, mice that survived B16 melanoma after CPS treatment exhibited increased survival against B16 melanoma re-challenge 40 d post-primary tumor challenge.…”

“…9 We recently reported that CPS therapy of a highly aggressive model of disseminated pancreatic cancer promoted long-term tumor-free survival of mice (>1 year). 11 Here, we report improved CPS therapy regimens and investigate CPS-triggered immunotherapeutic mechanisms that promote long-term protection against recurrence of pancreatic cancer.…”

The role of the tumour microenvironment in immunotherapy

“…Other major contributors of the immunosuppressive tumour microenvironment in PCs include suppressive myeloid cells and regulatory T cells (Tregs) (Morse et al 2009, Delitto et al 2016. The administration of the attenuated Toxoplasma gondii vaccine strain CPS in Panc02 cancer models activated proinflammatory myeloid cell populations and increased the expression of costimulatory molecules, the secretion of IL-12, and the recruitment of T cells into the tumour microenvironment (Sanders et al 2015). A modified ISOCOM vaccine was shown to be ineffective for advanced cancers due to Tregmediated immune suppression (Nicholaou et al 2009).…”