Abstract
BackgroundA 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.MethodsWhole 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.ResultsHere 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.ConclusionWe 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.
Highlights
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
Plasmodium infection significantly reduced the proportion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment To examine the MDSC subsets in the tumor microenvironment, single cell suspensions were prepared from the tumor tissues of Plasmodium. yoelli 17XNL (Py)-treated and untreated tumor-bearing mice, stained for MDSC markers and analyzed by flow cytometry
Our data indicated a significant reduction in the percentage of MDSCs (Fig.1d) (P < 0.01) in the tumor tissues of tumor-bearing mice treated with P. yoelli 17XNL (Py)-infected RBCs compared to the control
Summary
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. A key pathological feature of solid cancer is the massive mobilization and infiltration of immune cells into the lymphoid organs and the tumor microenvironment. In the peripheral lymphoid organs, there are more P-MDSCs than M-MDSCs; these P-MDSCs have a relatively modest suppressive activity and play a key role in the regulation of tumor-specific immune responses, facilitating the development of tumor-specific T-cell tolerance. MDSCs in the tumor microenvironment are more suppressive, mostly M-MDSC, and can differentiate into tumor- associated macrophages (TAMs)(reviewed in [12]). This further highlights the importance of novel strategies to inhibit multiple subsets of MDSCs both in the peripheral lymphoid organs and in the tumor microenvironment. Several MDSC-inhibiting drugs have been tested but only against splenic MDSCs, highlighting the need for the development of immune-enhancing drugs and interventions to target MDSCs in the tumor microenvironment
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