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Conniotet al. Nanocarriers for immunecell targetingand tracking by stromal cells, namely CXCL9 and CXCL10 (Gooden et al., 2011). Nevertheless, the inherent complexity of the immune regula- tion within tumormicroenvironment and the incomplete defi- nition of thosemultiplemechanisms demand additional efforts tocharacterize theseprocesses. Suchcharacterizationwouldsup- port the development of translational alternative immunother- apies (Mellman et al., 2011). For example, the presence of tumor-infiltrating T cells within tumor site may indicate that this particular type of tumor is a potential candidate for an immunotherapeutic strategy due to their ability to support the migration of T cells toward this particular region. However, the multiple factors involved in the immune system inhibition indicate that the use of complementary targeted strategies to improve thepresenceof anti-tumorTcells and theknock-down of immune inhibitorypathwaysmay lead tooptimal therapeutic approaches. Combinatory approaches for cancer therapy need indeed to consider the successful modulation of the tumor-associated cytokine network and cell communication within tumor microenvironment.Thiswillpreventtheinhibitionofanti-tumor responses and down-regulate the proliferation of malignant cells. The characterization of these immunoregulatory processes and the deeper understanding of the immunological features withintumormicroenvironmenthave fosteredtherecognitionof biomarkers.Suchrecognitionhasbeendrivingthedesignofnovel targeted therapies to block those pathways, including targeted nanomedicines to tumormicroenvironment to better avoid off- targetedeffects.Theanti-CTL4monoclonalantibodyipilumimab approved in 2011 by the US Food and Drug Administration (FDA) to treat patients with advanced melanoma, constitutes the first successful approach that targets one of those inhibitory pathways(Mellmanetal., 2011). Thedesignof these tumor-targeted systems is also influenced by a variety of specific features presented by this region, when compared to healthy tissues. Among those different properties, vasculature and pH have been the most explored toward the developmentof alternative and specific therapeutic nanosystems (Fernald and Kurokawa, 2013; Torchilin, 2011). Angiogenesis guarantees the supplyofoxygenanddifferentnutrients to tumor cells. It results from the action of different factors, as pro- angiogenic proteins, extracellular matrix proteins and matrix metalloproteinases. This process is fundamental for theprogres- sion of the disease and has guided the development of different targeted nanocarriers due to the particular morphology of the bloodvessels, as reviewedbyTorchilin (2011). In fact, abnormal architecture of blood vessel caused by incomplete angiogenesis allows the retentionofdifferentnanodelivery systemsspecifically at this particular tumor region, due to the so-called “Enhanced Permeability and Retention” (EPR), which will be described in SectionPassiveTargeting. CANCERIMMUNOTHERAPEUTICINTERVENTIONS Cancer immunotherapy has been explored for some decades. This term is often used to describe treatments based onmod- ulation of the immune system through “active” or “passive” approaches. The concept of immunotherapy relies on specific immunemechanismsandtargets,whichcouldconfergreatereffi- cacy and specificity with less toxicity. Therefore, improving the presence of anti-tumorT cells and the knock-downof immune inhibitorypathways, leading tooptimal therapeuticapproaches. ACTIVECANCERIMMUNOTHERAPY Active cancer immunotherapy or cancer vaccination consists in direct stimulation of the patient’s immune system so it can act against tumor cells. Unlike infectious disease vaccination, which efficiency is based mainly on neutralizing antibodies andB-lymphocyte response, cancer vaccination depends on the induction ofCTL responses and on the administration of TAAs tostimulateasystemic immuneresponse. Cancer vaccines are expected to induce a tumor specific immune response able to either eliminate themalignant cells or keep it under constant restraint, delaying tumor recurrence and prolonging survival. Both prophylactic and therapeutic vaccine- based cancer therapies havebeenproposed to enhance a specific immuneresponsetotumorcells, concerningDCactivity,assum- marized in Vacchelli et al. (2012). It has also been reported the prominence of DCs on CTL induction, thus becoming a striking target for cancer vaccination (Section Strategies forDC Targeting). The extensive research has led to engineered biotech molecules, such as proteins, peptides, antibodies and oligonu- cleotides,designedtoenhanceimmune-basedmechanisms,being promising players to re-shape the future of immunotherapeu- tic outcomes.However, as these candidatesmove toward clinical investigation, itbecomesclear that theirbiological effectdepends on thedevelopmentof a tool able toattain their transport across biological barriers. Accordingly, the potential of these bioactive molecules has pointed nanomedicines as an approach to ensure the target selectivity and safety required for their therapeutic in situefficacy, enabling theirclinical application. As discussed by Silva et al. (2013), an ideal vaccination strat- egy involves the administrationof themost immunogenicTAAs alongwith themost effective adjuvants, including delivery plat- forms.Thiswill prime the tumor- specificTcells, induce tumor- specific antibodies and kill tumor cells by host immune effector mechanisms. Several TAAs have been identified and characterized permit- ting their use in the design of targeted delivery systems (Bos et al., 2012; Engels et al., 2013). TAAs can be sorted as shared tumorantigens—whenpresent inmanytypesoftumorsandwith a distinct or absent expression on normal tissues (i.e., MAGE, GAGE and NY-ESO1)- or unique tumor antigens. These anti- gens result frompointmutations or splicing alterations and are expressedonlybya specific tumor(Higginset al., 2009;Pejawar- Gaddy et al., 2010).However, thosenewly identified antigens, as recombinant proteins, are usually weakly immunogenic, requir- ingmultipleadministrationsandtheirassociationwithadjuvants. It hasbeendescribed thatbothantigenandadjuvantmust act in a concertedway on the sameAPC,which can be provided by a singular delivery system (Schlosser et al., 2008; Krishnamachari etal., 2011;Raaijmakersetal., 2013). As previouslymentioned, the focus of cancer vaccines is the stimulation of a cell-mediated immunity, rather than humoral www.frontiersin.org November2014 |Volume2 |Article105 | 72