全國(guó)大學(xué)生數(shù)學(xué)模型聯(lián)試題的解課程-資料下載頁(yè)
2025-01-14 01:06本頁(yè)面
【正文】 as TGFβmolecules 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 smallchemical inhibitors,23 as well as the transfection of specific smallinterferingRNAs (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 adjuvantfor boosting the efficacy of DC/neoplastic cell ,27 HSPsgenerally 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 areimmunogenic, 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 havedemonstrated that the secretion of TGFβ1, IL10 and VEGRfrom whole cancer cells is significantly limited upon exposure topharmaceutical 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 tumorgrowth, promoted the upregulation of HSPs. HSPs exposed bycancer 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 theDC antigenpresenting Moreover, highmobilitygroup box 1 (HMGB1) passively released from dying neoplasticcells can stimulate antigen processing and presentation in DCs viaa TLR4dependent signaling ,32 Therefore, the exposureof CRT and the release of HMGB1 by ethanoltreated malignantcells enhance the immunogenicity of DC/cancer cell Importantly, fusions involving DCs and ethanoltreated cancercells activate T cells to produce high levels of IFNγ, boosting theelicitation of antigenspecific CTL response in In addition,HSP70peptide plexes derived from DC/cancer cell fusionsappear to possess superior immunogenic properties as paredwith similar plexes obtain from neoplastic Synergistic Effects of Fusions Generated
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