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Review
. 2007:25:267-96.
doi: 10.1146/annurev.immunol.25.022106.141609.

Immunosuppressive strategies that are mediated by tumor cells

Gabriel A Rabinovich  1 , Dmitry Gabrilovich, Eduardo M Sotomayor
Affiliations
Review

Immunosuppressive strategies that are mediated by tumor cells

Gabriel A Rabinovich et al. Annu Rev Immunol. 2007.

Abstract

Despite major advances in understanding the mechanisms leading to tumor immunity, a number of obstacles hinder the successful translation of mechanistic insights into effective tumor immunotherapy. Such obstacles include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, the activation of negative costimulatory signals, and the elaboration of immunosuppressive factors. In addition, we underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network; these include regulatory T cells, natural killer T cells, and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms may be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression.

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Figures

Figure 1
Figure 1. Conversion of tumor-induced T-cell tolerance to T-cell activation
In the immune response to tumors, BM-derived APCs capture tumor antigens at the tumor site and then migrate to the secondary lymphoid organs for presentation of antigenic peptides to tumor-specific T-cells. In the absence of inflammation and/or or in the presence of a “hostile” environment characterized by immunosuppressive factors at the tumor site, this process invariable leads to the induction of T-cell tolerance. However, generation of inflammatory APCs by either stimulating inflammatory pathways or by blocking negative regulators of inflammation in these cells can convert an APC/T-cell encounter from a tolerogenic event into a priming event in the tumor-bearing host.
Figure 2
Figure 2. Immunosuppressive strategies and immunological checkpoints exploited by tumors to evade immune responses
Tumors employ a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. These include defects in TCR proximal signals, tumor-induced impairment of the antigen presentation and processing machinery (red stars), activation of negative costimulatory signals in the tumor microenvironment (CTLA-4/B7, PD-1/PD-L1), elaboration of immunosuppressive factors (IL-10, TGF-β, galectin-1, gangliosides, PGE2), activation of proapoptotic pathways (FasL, TRAIL, IDO, RCAS1), inhibition of NK-cell mediated cytotoxicity (e.g release of soluble MICA) and inhibition of DC differentiation and maturation (STAT3, VEGF, IL-10, SOCS1, arginase). In addition, different regulatory cell populations contribute to this immunosuppressive network including CD4+CD25+ regulatory T-cells, inducible Tr1 cells, IL-13-producing NKT cells and distinct subsets of immature and mature myeloid and plasmacytoid DCs.
Figure 3
Figure 3. Differentiation of DCs and their contribution to the immunosuppressive network in cancer
DCs are differentiated in bone marrow from hematopoietic progenitor cells (HPC) alongside two major pathways. One is a myeloid-cell pathway that include common myeloid precursors (CMP) and immature myeloid cells (MDSC). The latter cells represent the population of immediate precursors of myeloid cells (granulocytes, macrophages, and DCs). In the periphery MDSC differentiate into immature DCs (iDC), which after encounter of different stimuli become activated or mature DCs (mDCs). The other pathway of DC differentiation includes common lymphoid precursors (CLP) and precursors of plasmacytoid DCs (ppDCs). These cells in the periphery become plasmacytoid DCs (pDC). Through a number of tumor-derived factors, tumors alter DC differentiation that results in increased production of pDC, accumulation of iDC, and immunosuppressive regulatory DCs and myeloid-derived suppressor cells (MDSC). All these populations of cells are able to suppress antigen-specific immune response in cancer via different mechanisms.
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