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Equally important, day 14 T cells from patients with cancer maintained their APC functionality, suggesting that patients-derived T cells may provide a valuable source for the generation of an autologous cellular vaccine


Mar 20, 2022

Equally important, day 14 T cells from patients with cancer maintained their APC functionality, suggesting that patients-derived T cells may provide a valuable source for the generation of an autologous cellular vaccine. Open in a separate window Figure 7 Influenza M1 cross-presentation to CD8+ T cells by day time 14 T cells. They resembled effector memory Nafamostat space T (TEM) cells and retained full features as assessed FzE3 by tumor cell killing as Nafamostat well as secretion of pro-inflammatory cytokines (IFN, TNF) and cell proliferation in response to activation with phosphoantigens. Importantly, day time 14 T cells indicated several APC-related cell surface markers and, in agreement, displayed potent APC functions. Day time 14 T cells from PBMC of individuals with cancer were equally effective as their counterparts derived from blood of healthy individuals and triggered potent CD8+ T cell reactions following control and cross-presentation of simple (influenza M1) and complex (tuberculin purified protein derivative) protein antigens. Of notice, and in obvious contrast to peripheral blood T cells, the ability of day time 14 T cells to result in antigen-specific T cell reactions did not depend on re-stimulation. We conclude that day time 14 T cell cultures provide a convenient source of autologous APC for use in immunotherapy of individuals with various cancers. generated, vaccine-loaded DC and injection of individuals with biologicals focusing on the patients personal DC (3). The former approach has the advantage of modifying cultured DC prior to their use as cellular vaccine. However, DC do not grow during culture and are scarce in peripheral blood. Therefore, a common strategy involves the generation of DC by culturing blood-derived monocytes for 6?days in the presence of IL-4 and GM-CSF [monocyte-derived DC (moDC)] (4). Again, this method does not yield Nafamostat unlimited numbers of moDC as the majority of cells die during the differentiation process. A hallmark of DC is usually their exquisite functional diversity underscored by the numerous unique DC subsets present in blood and peripheral tissue and their varied reactivity to maturation factors, including cytokines and microbial stimuli (5). These multiple factors may have limited the use of DC-based cellular vaccines in the medical center, explaining the paucity in approved cell products [except for Sipuleucel-T (6)], despite decades of fundamental and clinical research (3). T-antigen-presenting cells (APC), activated T cells with antigen-presentation function, might be a valuable alternative to moDC for use as cellular vaccines in the treatment of patients with malignancy (7). T-APC are generated during short-term activation of human peripheral blood T cells expressing V9V2-TCR. This particular T cell subset predominates in peripheral blood (1C5% of total T cells) and recognizes a class of non-peptide ligands, so-called phosphoantigens. The most potent phosphoantigen, (culture with V9V2-TCR+ T cells (abbreviated hereafter as T cells) provided the rationale for targeting these cells in current malignancy immunotherapy trials (14, 15). We here propose to explore the DC-like APC properties of T cells and to discuss the possibility of translating our findings into a novel type of cellular vaccine. The principles underlying the two T cell-based translational methods, i.e., tumor cell-killing and T cell activation, differ fundamentally from each other. Most notably, tumor cell-killing requires that infused T cells reach the sites of tumors in order to kill tumor cells during cell-to-cell contact. By contrast, the APC properties of T cells target endogenous T cells and, in order to do so, tumor-antigen-presenting T cells need to interact with tumor-specific T cells within secondary lymphoid tissues (spleen, lymph nodes). We do not anticipate that this mobilization of tumor-specific T cells in spleen and lymph nodes is usually hindered by those T cells that home to the tumor tissue. In fact, it may well be that tumor cell-killing by itself leads to prepared tumor-antigen-presenting T cells that may further enhance endogenous T cell responses. What is the evidence for DC-like properties of activated T cells? Much like tumor cell-killing, the APC functionality is the result of considerable studies facilitated by the fact that human peripheral blood T cells uniformly respond to HMBPP/IPP. Resting.