Mechanims of myeloid-derived suppressor cell-mediated immune regulation in cancer

Next to cardiovascular diseases, cancer is the most important cause of death in industrialized countries. Immunotherapy is a promising therapeutic avenue, but the efficiency of immune-based treatments is severely hampered by the induction of immunosuppressive mechanisms by the tumor. A major cause of immunosuppression is the fact that growing tumors are able to affect myelopoiesis through different tumor-derived factors, resulting in the accumulation of CD11b+ Gr-1+ myeloid-derived suppressor cells (MDSCs) in primary and secondary lymphoid organs as well as at the tumor site. MDSCs consist of two main subpopulations, known as monocytic MO-MDSCs and granulocytic PMN-MDSCs. The ability of MDSCs to suppress CD8+ T cell proliferation has been documented. However, whether these distinct MDSC subsets hamper all aspects of early CD8+ T-cell activation - including cytokine production, surface marker expression, survival and cytotoxicity - is currently unclear. In addition, the effect of MDSCs on dendritic cell (DC) function remains unexplored, despite the known importance of DCs for initiating and maintaining effective anti-tumor T-cell responses. First, we analyzed how MO- and PMN-MDSCs exactly influence the various features of CD8+ T-cell activation. Our data demonstrate that splenic MO- and PMN-MDSCs suppress antigen-driven CD8+ T-cell proliferation, but use distinct signaling pathways and effector molecules to do so. MO-MDSC-mediated T-cell suppression depends entirely on IFN-gamma, for which nitric oxide (NO) was one of the major mediators, while PMN-MDSCs display a suppressive mechanism that was mainly IFN-gamma- and NO-independent. In concordance with their ability to suppress CD8+ T-cell proliferation, MO- and PMN-MDSCs diminish interleukin (IL)-2 levels. Unexpectedly however, both MDSC populations stimulate IFN gamma production by CD8+ T cells on a per-cell basis, illustrating that some T-cell activation characteristics are actually stimulated by MDSCs. In addition, our data demonstrate that MO- and PMN-MDSCs differentially modulate the expression of (i) several adhesion molecules, (ii) Fas, which has a central role in the regulation of programmed cell death, and (iii) granzyme B. Together, these effects result in an altered CD8+ T-cell adhesiveness to the extracellular matrix and selectins, sensitivity to FasL-mediated apoptosis and cytotoxicity. Hence, our data clearly show that MDSCs intricately influence different CD8+ T-cell activation events in vitro, whereby some parameters are suppressed while others are stimulated. As defective CD8+ T-cell proliferation might result from altered T-cell priming by DCs, we next explored the capacity of MDSCs to alter the DC phenotype, both in vitro and in vivo. We show that resident as well as migratory DCs from draining lymph nodes - but not from spleen - of tumor-bearing mice, display a clear up-regulation of programmed cell death 1 ligand (PD-L1), which plays a major role in suppressing the immune system. We provide evidence that these alterations are induced locally by MO-MDSCs, but not by PMN-MDSCs. Accordingly, MO-MDSCs are the dominant MDSC population within tumor-draining lymph nodes. This preferential homing of MO-MDSCs is driven by the tumor via chemoattraction through chemokine receptor CCR2. In conclusion, this work brings new insights to the mechanisms of MDSC-mediated immune regulation in cancer, highlighting the existence of suppressive as well as stimulatory effects on various features of CD8+ T-cell activation while uncovering an influence of MO-MDSCs on the DC phenotype, which can be seen as a novel mode of MDSC-mediated immunoregulation