【正文】 derived molecules such as transforming growth factor β1 (TGFβ1). In particular,TLR2/4activated DCs (or the corresponding fusions): (1) exhibit increased expression levels of MHC class II molecules and CD86on the cell surface。 (2) manifest an improved fusion efficacy。 (3) produce elevated levels of IL12。 (4) simultaneously activateCD4+ and CD8+ T cells, which secrete high levels of interferon γ (IFNγ)。 (5) potently induce antigenspecific CTL activity。and (6) manifest a superior efficacy in inhibiting the generation of CD4+CD25+FOXP3+ Noheless, when DC/cancercell fusions are generated with neoplastic cells producing extremely high levels of TGFβ1, they inhibit the activity of CTLs in , incorporating the simultaneous activation of multiple TLRs and the blockade of immunosuppressive that are intrinsicallyproduced by DC/neoplastic cell fusions may significantly enhancethe therapeutic potential of this the Immunogenicity of Malignant CellsMost, if not all, malignant cells secrete multipleimmunosuppressive mediators such as TGFβ molecules normally inhibit the initiation of efficient CTLresponses,21 the microenvironment of malignant cells used forthe generation of DC/cancer cell fusions immunostimulatory. Several strategies to inhibit the production ofimmunosuppressive factors by cancer cells have been developed, including the administration of neutralizing antibodies22 and small chemical inhibitors,23 as well as the transfection of specific smallinterfering RNAs (siRNAs)24 or constructs coding for a solublevariant of the TGFβ Also heatshock proteins (HSPs), which have recently been implicated in the immunogenicity ofapoptotic and necrotic cells, might constitute effective adjuvant for boosting the efficacy of DC/neoplastic cell ,27 HSPs generally operate as chaperons for a wide panel of peptides, including antigenic peptides, and HSP/peptide plexes notonly can be efficiently taken up by DCs through specific receptors,but also can be presented in molecules the DC We have previously reported thatTLR2stimulated DCs fused with heattreated cancer cells are immunogenic, as demonstrated by: (1) the upregulation of multipleHSPs, MHC class I and II molecules, TAAs, CD80, CD86, CD83,and IL12。 (2) their ability producing high levels of IFNγ。 and (3) the capacity to efficientlyelicited antigenspecific CTL More recently, we have demonstrated that the secretion of TGFβ1, IL10 and VEGRfrom whole cancer cells is significantly limited upon exposure to pharmaceutical grade ethanol, a maneuver that does not reduce theevels of MHC class I molecules and TAAs on the cell Moreover, ethanol, employed at concentrations that affect tumrowth, promoted the upregulation of HSPs. HSPs exposed by cancer cells can be recognized by DCs via TLR4, facilitating theiractivation and promoting antigen processing and Of note, malignant cells that undergo immunogenic apoptosisectopically expose the Ca2+binding chaperone calreticulin (CRT) on the cell surface, allowing TAAs to efficiently traffic to the DC antigenpresenting Moreover, highmobility group box 1 (HMGB1) passively released from dying neoplastic cells can stimulate antigen processing and presentation in DCs via a TLR4dependent signaling ,32 Therefore, the exposure of CRT and the release of HMGB1 by ethanoltreated malignant cells enhance the immunogenicity of DC/cancer cell Importantly, fusions involving DCs and ethanoltreated cancer cells activate T cells to produce high levels of IFNγ, boosting the elicitation of antigenspecific CTL response in In addition, HSP70peptide plexes derived from DC/cancer cell fusions appear to possess superior immunogenic properties as pared with similar plexes obtain from neoplastic Synergistic Effects of Fusions Generated