A key pathological feature of solid cancer is the massive mobilization and infiltration of immune cells; into the lymphoid organs and the tumor microenvironment. Solid tumors are known for their ability to recruit and modify immune cells endothelial cells which form the tumor microenvironment. A growing body of evidence suggests that host immune cells with a suppressive phenotype pose a significant challenge to the success of immune-enhancing anticancer therapy.
Among these suppressor cells, myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) have shown to increase significantly in number in hosts with advanced malignancies. MDSCs are a heterogeneous population of cells that expand during cancer, inflammation, and infection, and have a remarkable ability to suppress T-cell responses. There are two main subsets of MDSCs; polymorphonuclear MDSCs (P-MDSCs), which are similar in phenotype and morphology to neutrophils, and monocytic MDSCs (M-MDSCs), which are similar to monocytes.
The peripheral lymphoid
In cancer, several differences in distribution and functions have observed in these MDSC subsets. 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. M-MDSCs in the peripheral lymphoid organs lack the capacity to differentiate into macrophages (MØ) and dendritic cells (DC).
In contrast, MDSCs in the tumor microenvironment are more suppressive; mostly M-MDSC, and can differentiate into macrophages. 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 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.
Implantation and analyzed using QPCR
Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells; harvested 17 days post tumor implantation and analyzed using QPCR; western blotting, flow cytometry, and functional assays. Differences between groups analyzed for statistical significance using Student’s t-test.
Here they found that Plasmodium infection significantly reduced the proportions of MDSC; 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 exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1.
Therefore they 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.