TY  - GEN
AV  - public
N2  - Several mechanisms have been proposed for profound immune impairments that accompany tumor development. Alteration in myelopoiesis that occur during tumor growth leads to the accumulation and recruitment of immunosuppressive cells, known as myeloid-suppressor cells (MDSCs). MDSCs have been characterized in cancer patients and tumor bearing mice based on their ability to suppress T cell responses. During tumor progression MDSCs accumulate in bone marrow, blood, peripheral lymphoid organs and in the tumor tissue. They represent a heterogeneous population of myeloid cells at different stages of differentiation. In mice these cells are characterized by the co-expression of the surface markers Gr-1 and CD11b. Within this population, two distinct MDSC subpopulations with clear morphological differences have been identified, comprising mononuclear cells (MO-MDSCs), which express Ly6C and the macrophage marker F4/80, and polymorphonuclear cells (PMN-MDSCs), which express Ly6G and do not display F4/80 surface expression.  The aim of this thesis was to determine the distribution of tumor-infiltrating and blood MDSC subsets as well as the molecular signature and function of genes differently regulated in MDSC subpopulations. We demonstrated that after subcutaneous injection of RMA-S tumor cells, both MDSC subsets accumulated in the tumor tissue. Gene expression profiling of blood and tumor-infiltrating MDSCs using whole genome microarrays revealed profound changes in the transcription profile between MDSC subsets in blood and tumor. Tumor-infiltrated MO-MDSCs displayed increased expression of genes involved in suppression, inflammatory responses and chemotaxis compared to blood MDSCs. We confirmed that differentially regulated genes at mRNA level were also differently expressed at protein levels and might play a significant role in MDSC function. In addition, tumor-infiltrating MDSCs showed an increased surface expression of TLR-4, CD14, and Dectin-2, suggesting a pro-inflammatory phenotype of these subsets in the tumor tissue. Stimulation of the CD14/TLR-4 complex with LPS resulted in an upregulation of the NKG2D ligand Rae-1, which might be involved in natural killer cell activation. Compared to blood MDSCs, the activity of suppressive factors such as arginase-1 and iNOS was increased in tumor-infiltrating MO-MDSCs. In addition, we observed that only tumor-infiltrating MO-MDSCs expressed high amount of several chemokines including three ligands of the chemokine receptor CCR5: CCL3 (MIP-1?), CCL4 (MIP-1?) and CCL5 (RANTES). Intra-tumoral injection of these recombinant chemokines resulted in an increased accumulation of regulatory  T cells and a lower CD8+/Treg ratio in the tumor tissue correlated with accelerated tumor growth and shortened survival of tumor-bearing mice. On the contrary, CCR5 deficient mice injected with RMA-S tumor cells showed reduced tumor growth and prolonged survival associated with high numbers of CD4+ and CD8+ T cells and an increased CD8+/Treg ratio detected in the tumor.  In summary, we demonstrated that tumor-infiltrating MO-MDSCs exerted key features to promote tumor progression. Increased expression of suppressive factors by MO-MDSC in the tumor tissue might directly downmodulate T cell responses, whereas chemokine secretion might induce the accumulation of tumor-infiltrating regulatory T cells, resulting in additive immune suppression. Those findings defined a new regulatory role of MDSCs in recruiting Tregs, which might be clinically relevant in developing novel immunotherapeutic strategies for cancer patients. 
A1  - Schlecker, Eva
KW  - MDSC 
KW  -  SubpopulationenMDSC 
KW  -  subsets 
KW  -  tumor
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/12318/
ID  - heidok12318
TI  - The role of tumor-infiltrating MDSC subsets in tumor progression
Y1  - 2011///
ER  -