Abstract
BackgroundMost tumor-associated antigens (TAA) currently used for immunotherapy of cancer are also expressed in normal tissues, which may induce tolerance and impair T cell-mediated immunity. However, there is limited information about how physiological expression in normal tissues alters the function of TAA-specific T cells.Methodology/Principal FindingsWe used a T cell receptor transgenic model to study how MDM2 expression in normal tissues affects the function of T cells specific for this TAA that is found at high levels in many different types of tumors. We found that some MDM2-specific T cells escaped thymic deletion and persisted in the peripheral T cell pool. When stimulated with antigen, these T cells readily initiated cell division but failed to proliferate and expand, which was associated with a high rate of apoptosis. Both IL-2 and IL-15 efficiently rescued T cell survival and antigen-specific T cell proliferation, while IL-7 and IL-21 were ineffective. Antigen-stimulated T cells showed impaired expression of the effector molecules CD43, granzyme-B and IFN-γ, a defect that was completely restored when T cells were stimulated in the presence of IL-2. In contrast, IL-15 and IL-21 only restored the expression of CD43 and granzyme-B, but not IFN-γ production. Finally, peptide titration experiments with IL-2 rescued T cells indicated that they were of lower avidity than non-tolerant control T cells expressing the same TCR.Conclusions/SignificanceThese data indicate that cytokines can rescue the antigen-specific proliferation and effector function of MDM2-specific T cells, although this does not lead to the recovery of high avidity T cell function. This study sheds light on possible limitations of immunotherapy approaches that target widely expressed TAA, such as MDM2.
Highlights
Mechanisms of both central and peripheral tolerance have evolved to silence T cells with specificity for self-antigen. Whilst these mechanisms of T cell tolerance reduce the risk of autoimmunity, they represent an obstacle to successful T cell-based cancer immunotherapy, as most T cell-recognised tumor antigens are expressed in some normal tissues [1,2,3,4,5]
The mean fluorescence intensity (MFI) of Vb7 staining for the T cells of Agpos mice was 3075 compared to 5543 in the Agneg control mice (Figure 1A)
The peripheral T cells responded to MDM2 peptides by initiating cell division, but the cells were unable to expand which correlated with a block in IL-2 production
Summary
Mechanisms of both central and peripheral tolerance have evolved to silence T cells with specificity for self-antigen. Most tumor-associated antigens (TAA) currently used for immunotherapy of cancer are expressed in normal tissues, which may induce tolerance and impair T cell-mediated immunity. We used a T cell receptor transgenic model to study how MDM2 expression in normal tissues affects the function of T cells specific for this TAA that is found at high levels in many different types of tumors. These data indicate that cytokines can rescue the antigen-specific proliferation and effector function of MDM2-specific T cells, this does not lead to the recovery of high avidity T cell function. This study sheds light on possible limitations of immunotherapy approaches that target widely expressed TAA, such as MDM2
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