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Conniotet al. Nanocarriers for immunecell targetingand tracking growthsuppressionandmetastasis(Chenetal.,2014b).Highlev- elsofindoleamine2,3-dioxygenasehavealsobeenfoundintumor microenvironment, reducing tryptophanpool levels,whichdrive TlymphocytestobearrestedatG1phaseofthecellcycle(Ahmad etal., 2004). TUMORMICROENVIRONMENT:TUMOR-INFLITRATINGIMMUNECELLS ANDRELATEDREGULATORYPATHWAYS The progress of cancer disease results from severalmechanisms developed by tumors to evade antitumor immune responses (SectionCancer immune evasionmechanisms), which has been associatedmostly to tumormicroenvironmentmolecular path- waysandinfiltratingcellsat thisparticularregion,ratherthanthe ignoranceanddefectsofanti-tumorTcells (Gajewskietal.,2013; Ma et al., 2013). In fact, the presence of different cells and their dynamic interactionwithmalignant cells have aprofound effect on tumorprogression (Mishra et al., 2010;Bussolati et al., 2011; Cortez-Retamozoetal., 2012;RahirandMoser,2012). It iswidelyaccepted that thedensityofTcell infiltrateswithin tumormicroenvironment is the most important factor to pre- dictcancerpatients’ survival (Eerolaetal.,2000;Obleetal.,2009; Mahmoudet al., 2011).Nevertheless,macrophages are also cur- rently recognizedas a fundamental cell type.As aheterogeneous population,itsdualfunctiontowardcancerisdeterminedbytheir polarization status (Mantovani and Sica, 2010). Macrophages are regulated by transcription factors, whichwill lead to differ- ent phenotypes of tumor-associatedmacrophages (TAMs). M1 and M2 have been already characterized, being associated to the pathogenesis of several diseases, namely inflammatory and tumordiseases (Sica et al., 2006). Indeed, pro-inflammatoryM1 macrophages, afterbeingactivatedby IFN-γ, favorTh1 immune cell activity andpotentiate theeradicationofmalignant cells.On the other hand,M2 phenotype enables Th2 immune responses andregulate tissuerepair,presentingpro-tumoralabilities insev- eral tumor types (Sica andMantovani, 2012; Cornelissen et al., 2014). Moreover, the production of several cytokines, such as IL-1, IL-6, IL-10,VEGF, andTGF-βbyM2TAMselicits thepro- liferation andmetastasis of tumor cells (Biswas andMantovani, 2010). As a result, it has been described that the number ofM2 macrophages and the overallM2/M1 ratio of TAMs are impor- tant predictors of survival for distinct types of cancers, namely melanoma (Erdag et al., 2012;Herwig et al., 2013), ovarian can- cer(Lanetal.,2013;Colvin,2014),T-cell (Niinoetal.,2010),and B-cell lymphomas (Nam et al., 2014), breast (Leek et al., 1996) andpancreaticcancer(Inoetal., 2013). It is important tomentionhowever that theM1andM2clas- sification of TAMs is not static, being usually very complex and seems to be dictated by several mediators resultant from cel- lular cross-talk and environmental conditions (Cai et al., 2012; Escribese et al., 2012; Shimeet al., 2012). Even tough, the causes underlying thedifferentiationofTAMstoM1orM2phenotypes are not yet fully understood. Type I interferon pathway seems tobe fundamental for the activationof innate immune response against tumorcells.However, theproductionof type I interferon byDCsremainanunderexplored issue(Fuertesetal., 2011). DCs are alsopresentwithin tumormicroenvironment,where they can recognize and capture live and dying tumor cells (Dhodapkar et al., 2008; Ma et al., 2013). Their presence in tumorsofdifferent stagesandgradescorrelates toprolongeddis- ease survival and lower invasiveness, as reviewed inPalucka and Banchereau (2012). Even though, some of this heterogeneous hematopoietic lineage displays anti-tumor effects while others present immunosuppressive functions at tumor site. Actually, tumor-infiltratingDCs functionalitymay vary according to the combinationof environmental factors andpathwayswithinvari- able tumor site.AmongDCsubsets, it shouldbeemphasized the roleof tumor-infiltratingplasmacytoidDCs(pDCs)andCD8α+ DCslineage,being thefirstoftenrelated toTcell tolerance,while the latter is in fact particularly efficient in the cross-presentation of antigens via MHCI pathways and thus in cytotoxic T-cell immunity(Hildneretal.,2008;Fuertesetal.,2011;Watkinsetal., 2011). The characterization of different solid tumors, asmelanoma, showed thepresenceof tumor-infiltrating lymphoid cell lineage, includingCD8+Tcells. Their function ismainly compromised by immune system-inhibitorypathways at tumormicroenviron- ment, enablingT cell anergy (Gajewski et al., 2013). It has been reported thepresenceofhighamountsofCD4+Foxp3+ regula- toryTcells(Tregcells)thatareattractedbythechemokineCCL22 via CCR4 (Toulza et al., 2010; Spranger et al., 2013). However, the functionofT-cell subsetswithin tumormicroenvironment is highlycomplex,dependingonseveral factors, suchas the typeof receptorsprimed. Another hypothesis for the presence of T cells within the tumormicroenvironmentofcertaintumorsmayberelatedtothe formationofalymphnode-likestructurecalledtertiarylymphoid tissues, where it is possible to findB cells, T cells and activated DCs (Messina et al., 2012). Still, it is not clear if the formation of those lymphoidstructures is involved intumorgrowth invivo. On theotherhand, tumor-infiltratedTcells can expressCCL21. CCL21 is related to tumor tolerance by stimulatingnaïveT cells towhich thepresentationofTAAswillnotbeefficientdue to the absenceofco-stimulatory factors (Shieldsetal., 2010). NK,NKTandγδTcellsalsoseemtohaveanimportantrole in theimmunomodulationoftumormicroenvironment(Pengetal., 2007;Mishra et al., 2010;Marcu-Malina et al., 2011; Liu et al., 2012). The antitumor effect ofNKhas been linked to solid and hematopoietic tumors, whileγδTcells andNKTcells have been involved in tumor inhibition.However, they showimmunoregu- latory functions incertain circumstances that arenot completely known(Pengetal.,2007;Mishraetal.,2010;Marcu-Malinaetal., 2011; Liu et al., 2012).Apromising strategyhasbeen focused in the stimulation of DCs by α-galactosylceramide to primeNKT, promoting theproductionof IFN-γ (Shimizuetal., 2013). Besides these cells, tumor stroma has also been associated with tumor growth and includes different elements as colla- gen, endothelial cells, fibroblast and severalmacrophage subsets, whichcontributesfortumorimmuneevasion.Inaddition,higher levelsofangiogenic factorswere foundintumorswhere thepres- ence of tumor-infiltrating T cells is poor (Danhier et al., 2010). Themajorimmunosuppressivemechanismsincludethesecretion of IL-10,TGF-β, andCCL22byM2macrophages (Condeelis and Pollard,2006).ThetraffickingofTcellswithintumormicroenvi- ronmenthasbeenrelatedtothesecretionofdifferentchemokines Frontiers inChemistry | ChemicalEngineering November2014 |Volume2 |Article105 | 71