Seite - 69 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking mostly directed to the destruction of tumors by strengthening the immune system (Rosenberg, 2001; Palucka andBanchereau, 2012). The recognition of the crucial role of T-lymphocytes in can- cer for immune-mediated treatments has contributed to the exhaustivecharacterizationof tumor-associatedantigens(TAAs). Of particular interest are the cytotoxic T Lymphocytes (CTL), whichuponantigenrecognitioncanselectively targetanddestroy malignant cells presenting epitopeswhichhavebeen recognized. However, their isolated response is often not enough and the development of an optimal cancer vaccine seems to be depen- dent on an effective stimulation and cooperation between CTL and T helper (Th) cells specific for a tumor epitope (Fong and Engleman, 2000; Banchereau et al., 2001; Palucka and Banchereau,2012). In addition to the evolutionof tumor immunology, therehas beenprogress in thedevelopmentofnanodeliverysystems.These systems have the potential to overcome some of the drawbacks ofcurrentchemotherapyandradiotherapytherapies.Asreviewed byChowandHo(2013),nanosystemscandisplayimprovedphar- macokineticsandtargetingoftissuesandcells toenhanceefficacy, specificity and lower toxicity.Accordingly,nanosystemsdesigned totarget immunemoleculesandcellsmayallowthedevelopment ofapproachesthatwillusethepatient’s immunesystemasamore specific tool tofightcancer. Nano-based platforms have also been explored for immune cell labeling, using fluorescence and molecular imaging tech- niques. As a result, immune cellmechanisms engaged in cancer development and tumor metastasis can thus be better under- stood, guiding the development of advanced platforms able to specifically targetandtrack immunecells. CANCERANDTHEIMMUNESYSTEM INNATEANDADAPTIVEIMMUNITYTOCANCER The immune system is composedof twomainbranches—innate and adaptive immune responses. The innate immunity is a non-specific first line defense of our body against antigens. It comprises anatomic, physiologic, phagocytic, and inflammatory barriers, such as skin ormacrophages and neutrophils. On the otherhand, adaptive immunity is ahighly specificcomponentof theimmunesystem,whichisstimulatedbyaspecificantigenchal- lengetotheorganism.Still, the latter isnot independent fromthe innate response, since antigen-presenting cells (APCs), involved in innate immunity, play a pivotal role in specific immunity activation(RoittandDelves,2001;Kindtetal., 2006). Dendriticcells(DCs),alongwithmacrophagesandBlympho- cytes, are described as APCs (Roitt and Delves, 2001; Gogolak et al., 2003; Kindt et al., 2006). DCs are the most powerful “professional” APCs, being present in the majority of mam- malian tissues and acting as an interface between innate and adaptive immunity. They control and regulate the immune sys- tem.DCs are organized in an intricate network throughout the human lymphatic and non-lymphatic tissues, having different functions, depending on their stage ofmaturation (Banchereau et al., 2003; Bodey et al., 2004; Palucka andBanchereau, 2012). Non-activated immature DCs capture antigens and induce tol- erance in the steady state, whereasmature antigen-loadedDCs can prime an antigen-specific immune response. DCs can also becategorized in threemainsubsets—(i)Langerhanscells (LCs); (ii) interstitialDCs(intDCs)and(iii)plasmocytoidDCs(pDCs). Thoughallsubsetsderivefromthesameprecursorcells—CD34+ hematopoietic stem cells, found in themarrow—they are origi- natedfromtwomajordistinctpathways(Banchereauetal.,2003). LCsandintDCsarisefromthemyeloidpathway,areCD11c+and bothproduceIL-2.LCsarepresent instratifiedepithelia, likeskin andupper airways, whilst intDCsmaybe found in all other tis- sues.Additionally, intDCscansecrete IL-10andelicitnaïveBcell differentiation (Gogolaket al., 2003).Theotherparallel pathway originatesphenotypicallyCD11c−pDCswith the ability topro- duce high amounts of type I interferon and tomodulate T cell differentiation(Gogolaketal., 2003). In tumor immunology, DCs are crucial for the presentation ofTAAsandtostimulate the immunesystemafterDCactivation (PaluckaandBanchereau,2012).DCspatrol thedifferent tissues, processingexogenousandendogenousantigensthatarethenpre- sented toT lymphocytes, afterDCmaturation. Thematuration process ofDCscanbe induceddirectly through“danger signals” detectedbypattern recognition receptors (PRRs)or triggeredby thepresenceof inflammatorymediators, suchasTNF-αor IL-1β (Bodeyetal., 2004). AntigenpresentationtoTlymphocytesbyDCsoccursthrough T-cell receptors (TCRs) that recognize antigens bound tomajor histocompatibility complex (MHC) molecules. MHC proteins can be sorted in twomain groups:MHC class I—expressed on themembraneof themajorityofnucleatedcells invertebrates— andMHCclass II, only found inAPCs (LevineandChain, 1991; Bodey et al., 2004). After the contact of a naïve T cell with MHC-antigen complex, T cells proliferate and differentiate in bothmemoryTcells andeffectorTcells. EffectorTcellsmaybe divided in T helper (Th—CD4+) or T cytotoxic (Tc—CD8+) cells (Guermonprez et al., 2002;Gogolak et al., 2003).The stim- ulationofTccells can lead to thegenerationofCTLs that secrete lowlevelsofcytokines,unlikeTccells.However, theydisplaycell- killing action, controlling and eliminating cells that exhibit any type of antigen, such as infected cells or tumor cells (Gogolak etal.,2003).Other innate lymphocytessubsets, suchasγδTcells, natural killer (NK) and natural killer T (NKT) cells, have been reportedasbeingengagedinacompleximmunomodulatorynet- work,displayinganti-tumoractivity.Preclinical studiesdescribed that NKT cells can exhibit anti-tumor or immune-regulatory mechanisms(Gajewskietal., 2013). The interactionamongBcells,Tcells andmatureDCsresults inanintegratedimmuneresponse.Therefore,DCmigrationfrom the tumor site of antigen capture to secondary lymphoidorgans can thus greatly broaden antigen-specific T cell responses, pro- moting effective anti-tumor immune responses that will lead to tumor rejection and regression (Palucka and Banchereau, 2012). Apromisingnano-basedstrategyhasbeendesignedinorderto develop syntheticDCs forTcell activationand immunotherapy, basedon semi-flexible andfilamentouspolymers (Mandal et al., 2013).Effectiveantitumor-immuneresponsesarethusdependent on the development of alternative systems to deliver antigens to DCsandpromote their presentation toTcells. These factors are Frontiers inChemistry | ChemicalEngineering November2014 |Volume2 |Article105 | 69