Dataset Information

Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model.

ABSTRACT:

Background

A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown.

Methods

Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Differences between groups were analyzed for statistical significance using Student's t-test.

Results

Here we found that Plasmodium infection significantly reduced the proportions of MDSCs and Tregs in the lung tumor tissues of the treated mice by downregulating their recruiting molecules and blocking cellular activation pathways. Importantly, CD8⁺ T cells isolated from the tumors of Plasmodium-treated mice exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1.

Conclusion

We reveal for the first time, the effects of Plasmodium infection on the expansion and activation of MDSCs and Tregs with a consequent elevation of CD8⁺T cell-mediated cytotoxicity within the tumor microenvironment and hold great promise for the development of effective immunotherapeutic strategies.

SUBMITTER: Adah D

PROVIDER: S-EPMC6461823 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model.

Adah Dickson D Yang Yijun Y Liu Quan Q Gadidasu Kranthi K Tao Zhu Z Yu Songlin S Dai Linglin L Li Xiaofen X Zhao Siting S Qin Limei L Qin Li L Chen Xiaoping X

Cell communication and signaling : CCS 20190412 1

<h4>Background</h4>A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown.<h4>Meth ...[more]

PMID: 30979375

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Project description:BackgroundImmune escape remains a major challenge in the treatment of malignant tumors. Here, we studied the mechanisms underlying immune escape in the tumor microenvironment and identified a potential therapeutic target.MethodsPathological specimens from patients with liver cancer, soft tissue sarcoma, and liver metastasis of colon cancer were subjected to immunohistochemistry analysis to detect the expression of programmed death-1 (PD-1) in the tumor microenvironment (TME). Additionally, the expression of regulatory T cells (Tregs) and long non-coding RNAs (lncRNAs), such as highly upregulated in liver cancer (HULC) was evaluated by fluorescence in situ hybridization, and the relationship between HULC, Treg cells, and PD-1 was determined. The animals were divided into H22 hepatic carcinoma and S180 sarcoma groups. Each group was divided into Foxp3-/-C57BL/6J and C57BL/6J mice. Thereafter, mice were inoculated with 0.1 ml S180 sarcoma cells or 0.1 ml H22 hepatoma cells, at a concentration of 1 × 107/ml. The number of splenic CD4+CD25+Foxp3+ T cells was detected by flow cytometry, and serum interleukin-10 (IL-10) and transforming growth factor β1 (TGF-β1) levels were detected using a Luminex liquid suspension chip. Expression of PD-1, fork head box P3 (Foxp3), and HULC in the TME, were analyzed and the therapeutic effect of inhibiting the lncRNA HULC-Treg-PD-1 axis in malignant tumors was determined.ResultsHigh expression of lncRNA HULC promotes the proliferation of Treg cells and increases PD-1 expression in the tumor microenvironment. The HULC-Treg-PD-1 axis plays an immunosuppressive role and promotes the proliferation of malignant tumors. Knocking out the Foxp3 gene can affect the HULC-Treg-PD-1 axis and reduce PD-1, IL-10, and TGF-β1 expression to control the growth of malignant tumors.ConclusionThe lncRNA HULC-Treg-PD-1 axis promotes the growth of malignant tumors. This axis could be modulated to reduce PD-1, IL-10, and TGF-β1 expression and the subsequent immune escape. The inhibition of immune escape in the tumor microenvironment can be achieved by controlling the LncRNA HULC-Treg-PD-1 axis.

Project description:Myeloid-derived suppressor cells (MDSC) are induced by and accumulate within many histologically distinct solid tumors, where they promote disease by secreting angiogenic and immunosuppressive molecules. Although IL1β can drive the generation, accumulation, and functional capacity of MDSCs, the specific IL1β-induced inflammatory mediators contributing to these activities remain incompletely defined. Here, we identified IL1β-induced molecules that expand, mobilize, and modulate the accumulation and angiogenic and immunosuppressive potencies of polymorphonuclear (PMN)-MDSCs. Unlike parental CT26 tumors, which recruited primarily monocytic (M)-MDSCs by constitutively expressing GM-CSF- and CCR2-directed chemokines, IL1β-transfected CT26 produced higher G-CSF, multiple CXC chemokines, and vascular adhesion molecules required for mediating infiltration of PMN-MDSCs with increased angiogenic and immunosuppressive properties. Conversely, CT26 tumors transfected with IL1β-inducible molecules could mobilize PMN-MDSCs, but because they lacked the ability to upregulate IL1β-inducible CXCR2-directed chemokines or vascular adhesion molecules, additional PMN-MDSCs could not infiltrate tumors. IL1β-expressing CT26 increased angiogenic and immunosuppressive factors of tumor-infiltrating MDSCs, as did CT26 tumors individually transfected with G-CSF, Bv8, CXCL1, or CXCL5, demonstrating that mediators downstream of IL1β could also modulate MDSC functional activity. Translational relevance was indicated by the finding that the same growth factors, cytokines, chemokines, and adhesion molecules responsible for the mobilization and recruitment of PMN-MDSCs into inflammatory CT26 murine tumors were also coordinately upregulated with increasing IL1β expression in human renal cell carcinoma tumors. These studies demonstrated that IL1β stimulated the components of a multifaceted inflammatory program that produces, mobilizes, chemoattracts, activates, and mediates the infiltration of PMN-MDSCs into inflammatory tumors to promote tumor progression.

Dataset Information

Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model.

Background

Methods

Results

Conclusion

Publications

Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model.

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