Seite - 70 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking important tobear inmindwhendeveloping an effective vaccine (Gajewskietal., 2013). CANCERIMMUNEREGULATIONANDEVASIONMECHANISMS Cancer immunosurveillance Paul Ehrlich proposed the concept of the immune system as a useful strategy against cancer, in the beginning of theTwentieth century (Ehrlich,1909). Somedecadesafter,ThomasandBurnet postulated the immunosurveillance theory based on Ehrlich’s hypothesis. Cancer arousal was suggested to be caused by the lack of efficiency of the immune system or themodification in antigen expressionof tumor cells, leading to its evasion (Burnet, 1957;Thomas,1982).ThomasandBurnetalsoclaimedthatanti- tumorimmuneresponsegenerallyhappensatanearlystageofthe cancer development (Burnet, 1957; Thomas, 1982). Therefore, once the tumor has grown, it escaped the immunosurveillance barrier and started developing additionalmechanisms to evade from the immune system (Ahmad et al., 2004). Nevertheless, Strutman’s later studies showed that cancer susceptibility of immune-competent mice was similar to that observed inmice with major immunodeficiency, setting against the immuno- surveillance hypothesis (Shankaran et al., 2001; Dunn et al., 2002). In the beginning of this century, the immunosurveil- lance hypothesis was revised, as several studies have shown that the immune systemmay not only destroy tumor cells but also shape theirphenotypes, leading to reductionof immunogenicity (Shankaranetal., 2001;Dunnetal., 2002;Schreiberetal., 2011). Currently, there is increasing evidence that tumorcells canbe recognized and destroyed by the immune system, as developing tumorcellsoftenco-express tumorantigensand ligands foracti- vatingreceptors(Schreiberetal.,2011).Therefore, it is important to describe which immune components display major roles in tumor rejection. It is also important to clarify the appropriate timeandefficient typeofaction(SwannandSmyth,2007). Cancer immunoeditingandcancer-relatedinflammation AsreviewedbySchreiberetal. (2011),cancer immunoeditingcan bedivided in threedifferentphases: “elimination,”“equilibrium” and“escape.” In the first stage—“elimination”—both innate and adaptive immunitiesactcombinedtoidentify theformationoftumorcells and todestroy them, resembling the immunosurveillance theory. Althoughmanymechanisms are still poorly known, it has been reported that cytokines, “danger signals” andDCs have impor- tant roles in this phase (Sims et al., 2010; Vesely et al., 2011). It has also been suggested that the required components for an effective “elimination” depend on specific characteristics of the tumorcells, suchas itsoriginoranatomical location(Simset al., 2010). If the“elimination”stage iswell succeeded, tumorcellsare destroyed, constituting an endpoint for cancer immunoediting (Schreiberetal., 2011;Veselyetal., 2011). The next stage—“equilibrium”—is described as a period of tumor latency. In other words, when a tumor cell survives the elimination phase, the adaptive immune response can control tumor cell growth and shape its immunogenicity. “Equilibrium” isbelieved tobe the longestphaseof cancer immunoeditingpro- cess. It seemstoallowcancercells toreside inpatients’bodyeven decades before it restarts to grow and become clinically evident (Schreiberetal., 2011;Veselyetal., 2011). The third phase—“escape”—occurs when tumor cells have developed the ability to evade the mechanisms of recognition of the immune system and/or their elimination. Tumor cells are thought to progress from “equilibrium” phase to “escape” through several mechanisms and/or pathways. For instance, an alterationinimmunesystemresponse,whichmaybetriggeredby cancer-induced immunosuppression or a change in tumor cells induced by immunoediting, or even immune system deteriora- tion(Schreiberetal., 2011;Veselyetal., 2011). Cancer immuneevasionmechanisms Cellularimmunityhasbeenshowntoplayamajorroleinthecon- trol of tumor generation. Even though, recent findings revealed that tumors oftenmanage to evade it through several different mechanisms.Ithasbeenreportedthatthereisareductionoreven loss of MHCI molecules, mostly associated to gene mutations or impairmentofMHCI-dependentantigenprocessing (Garrido andAlgarra,2001;Ahmadetal.,2004;Veselyetal.,2011).Inaddi- tion,anantigenicdrift incancercellshas latelybeenobservedand appears toberelatedwith themutation, lossordown-expression of TAAs in tumor cells (Uyttenhove et al., 1997; Ahmad et al., 2004). Similarly, the lack or reduction of the expression of co- stimulatory patterns by tumor cells direct T lymphocytes to an anergy state. Thesemechanisms altogether seem to reduce and difficult thedetectionofcancercellsbyCTLsandNKcells,which consequently leads to tumorgrowth(Ahmadetal., 2004). Alterations inapoptoticreceptorsignalingseemtohelptumor cells to evade the immune system. Molecules such as phos- phatidylinositol3-kinase (PI3K),proteinkinaseBandFas ligand (FasL)havemodifiedexpressionandmightbe implicated in this process (Davidsonetal., 1998;Osakietal., 2004). Tumor eradication is also dependent on the manipulation of immunosuppressive properties of tumormicroenvironment, where inducingand suppressing cytokine imbalance impairsDC activation and maturation, compromising immune cell effec- tor properties and supporting tumor growth. Tumor cells can indeed secrete immunosuppressive molecules, including vascu- lar endothelial growth factor (VEGF), IL-10 and transforming growth factor-β (TGF-β) (Fortis et al., 1996; Tsushima et al., 1996; Oyama et al., 1998). VEGF appears to be responsible for down-regulation of NF-κB expression, which interferes in DC maturation and differentiation, limiting the immune response againsttumorcells(Oyamaetal.,1998).Ontheotherhand,TGF- β1 is an immunesuppressivecytokine involved in theconversion ofCD4+Tcells intoimmunosuppressiveTregulatory(Treg)cells thataremainlyproducedbyDCsandtumorcells (Zou,2005). These immunosuppressivemoleculesare interesting targets to achieve tumorgrowth inhibitionandmightbeaveryuseful tool for cancer immunotherapy.Theuseofnanoparticles (NPs) con- taining small interferingRNA(siRNA) toknock-downTGF-β in the tumormicroenvironment has resulted in increased levels of CD8+Tcells and lower number of Treg cells, leading to tumor growth inhibition by 52% (Xu et al., 2014). A similar strategy usingpolyethylenimine-capped silicaNPs carryingVEGFsiRNA has beendesigned as a highly effective approach for lung cancer www.frontiersin.org November2014 |Volume2 |Article105 | 70