Neutralizing Regulatory T Cells Shevchenko, Ivan; Umansky, Viktor
Frontiers in Cancer Immunology,
April 2015, Letnik:
1, Številka:
1
Book Chapter
The maintenance of peripheral tolerance against self and environmental
antigens needs regulatory T cells (Treg) that deploy a variety of suppressive
mechanisms to control potentially harmful ...inflammatory and autoimmune reactions.
These mechanisms include production of suppressive cytokines and small molecules,
expression of inhibitory receptors as well as direct cytolysis and intracellular transfer of
second messengers. However, the tumors may hijack Treg immunosuppressive function
to escape the anti-cancer immune responses. Expression of self- or altered-self antigens
on tumor cells may drive Treg expansion and enhance their suppressive activity.
Therefore, Treg-mediated immunosuppression represents one of the main hurdles to the
anti-tumor immunity accounting for the failure of anti-tumor therapies including the
vaccination and adoptive cell transfer. It has been shown that inhibition of Treg
development, survival, and function can alleviate tumor-induced immunosuppression
and improve the efficacy of anticancer immunotherapy. Here we discuss current
strategies of targeting Treg development and function, including Treg depletion,
inhibition of extracellular adenosine production and modulation of signaling pathways
in Treg through cell surface receptors.
Elimination of mature functional dendritic cells represents one of the most important mechanisms of tumor immune evasion. It includes inhibition of dendritic cell differentiation and maturation as ...well as a direct induction of apoptosis in dendritic cells or their precursors. Numerous experimental and clinical studies revealed that different factors produced by both tumor and stromal cells, such as VEGF, IL-10, TGF-β, gangliosides and other, could induce apoptotic death of dendritic cells and stimulate spontaneous apoptosis both in vitro and in vivo. Both mechanisms, i.e. suppression of dendritic cell differentiation and dendritic cell apoptosis, can contribute to the reduction of dendritic cell numbers observed in cancer, which was shown to be associated with the tumor progression. Therefore, neutralization of the suppressive tumor microenvironment will allow a proper dendritic cell differentiation from their precursors and protect functionally active dendritic cells from apoptotic death.
Extracellular vesicles (EVs) have been shown to transfer various molecules, including functional RNA between cells and this process has been suggested to be particularly relevant in tumor-host ...interactions. However, data on EV-mediated RNA transfer has been obtained primarily by in vitro experiments or involving ex vivo manipulations likely affecting its biology, leaving their physiological relevance unclear. We engineered glioma and carcinoma tumor cells to express Cre recombinase showing their release of EVs containing Cre mRNA in various EV subfractions including exosomes. Transplantation of these genetically modified tumor cells into mice with a Cre reporter background leads to frequent recombination events at the tumor site. In both tumor models the majority of recombined cells are CD45+ leukocytes, predominantly Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs). In addition, multiple lineages of recombined cells can be observed in the glioma model. In the lung carcinoma model, recombined MDSCs display an enhanced immunosuppressive phenotype and an altered miRNA profile compared to their non-recombined counterparts. Cre-lox based tracing of tumor EV RNA transfer in vivo can therefore be used to identify individual target cells in the tumor microenvironment for further mechanistical or functional analysis.
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