No abstract

Tumor‐associated factors are related to increased accumulation of CD11b+Gr1+myeloid‐derived suppressor cells (MDSCs). However, the exact mechanism of how genetic factors control the expansion of MDSCs in tumor‐bearing hosts remains elusive. Herein, we found that tumor‐associated MDSCs and their subsets, mononuclear MDSCs and polymorphonuclear MDSCs, have decreased expression of miR‐223 when compared to CD11b+Gr1+ cells from the spleen of disease‐free mice. With the differentiation of CD11b+Gr1+MDSCs from bone marrow cells (BMCs) upon exposure to tumor‐associated factors, the expression of both pri‐miR‐223 and mature miR‐223 was downregulated, indicating that the expression of miR‐223 could be regulated by tumor‐associated factors. Interestingly, miR‐223 remarkably inhibits differentiation of BMCs into CD11b+Gr1+MDSCs in the presence of tumor‐associated factors by targeting myocyte enhancer factor 2C (MEF2C). Using reconstituted s.c. tumor models, miR‐223 also suppresses accumulation of CD11b+Gr1+MDSCs, whereas its targeting molecule MEF2C increases the number of MDSCs. Tumor growth is slower in mice infused by miR223‐engineered BMCs than in mice infused with control transfected BMCs. As miR‐223 and its target molecule MEF2C are highly conserved between mice and humans, the modulation of miR‐223 in tumor‐induced CD11b+Gr1+MDSCs may exert an important role in controlling the increased accumulation of CD11b+Gr1+MDSCs in patients with tumor.

Dendritic cell (DC) function is negatively affected by tumors and tumor-derived factors, but little is known about the underlying mechanisms. Here, we show that intracellular SOCS3 in DCs binds to pyruvate kinase type M2 (M2-PK), which plays a critical role in ATP production through glycolysis. The interaction of SOCS3 with M2-PK reduced ATP production and impaired DC-based immunotherapy against tumors. Thus, SOCS3, which has been shown to be upregulated by tumor-derived factors, interacts with M2-PK to decrease ATP production, causing DC dysfunction. These dysfunctional DCs have a reduced ability to present antigens. Alteration of DC metabolism mediated by SOCS3 represents a novel mechanism for DC dysfunction in the tumor microenvironment. Cancer Res; 70(1); 89-98. ©2010 AACR.

No abstract

CD8-positive T cells respond to small antigenic peptide fragments presented on class I major histocompatibility complexes (MHCs). Those specific T cell epitopes capable of precipitating a cellular immune response are either derived from (altered) self (i.e. they are autoimmune- or cancer-associated) or come from foreign sources (i.e. they are pathogen-associated). Identification of T cell epitopes provides elementary information that can be employed in technologies that monitor and predict the likely outcome of an immune response, as well as in therapeutic and vaccine development efforts. The coexistence between host and pathogen has largely driven the diversification of both their systems of immune surveillance and their antigenic determinants, respectively. In this review, we discuss the multitude of factors that introduce diversity to the T cell response from both sides of the host-pathogen interaction. Furthermore, we provide an overview of a variety of commonly employed methods and tools to characterize class I MHC restricted antigen presentation and recent endeavors towards the harmonization of reporting data concerning T cell responses.