Abstract
BackgroundCancer vaccines are designed to activate and enhance cancer-antigen-targeted T cells that are suppressed through multiple mechanisms of immune tolerance in cancer-bearing hosts. T regulatory cell (Treg) suppression of tumor-specific T cells is one barrier to effective immunization. A second mechanism is the deletion of high avidity tumor-specific T cells, which leaves a less effective low avidity tumor specific T cell repertoire available for activation by vaccines. Treg depleting agents including low dose cyclophosphamide (Cy) and antibodies that deplete CD25-expressing Tregs have been used with limited success to enhance the potency of tumor-specific vaccines. In addition, few studies have evaluated mechanisms that activate low avidity cancer antigen-specific T cells. Therefore, we developed high and low avidity HER-2/neu-specific TCR transgenic mouse colonies specific for the same HER-2/neu epitope to define the tolerance mechanisms that specifically affect high versus low avidity tumor-specific T cells.Methodology/Principal FindingsHigh and low avidity CD8+ T cell receptor (TCR) transgenic mice specific for the breast cancer antigen HER-2/neu (neu) were developed to provide a purified source of naïve, tumor-specific T cells that can be used to study tolerance mechanisms. Adoptive transfer studies into tolerant FVB/N-derived HER-2/neu transgenic (neu-N) mice demonstrated that high avidity, but not low avidity, neu-specific T cells are inhibited by Tregs as the dominant tolerizing mechanism. High avidity T cells persisted, produced IFNγ, trafficked into tumors, and lysed tumors after adoptive transfer into mice treated with a neu-specific vaccine and low dose Cy to deplete Tregs. Analysis of Treg subsets revealed a Cy-sensitive CD4+Foxp3+CD25low tumor-seeking migratory phenotype, characteristic of effector/memory Tregs, and capable of high avidity T cell suppression.Conclusion/SignificanceDepletion of CD25low Tregs allows activation of tumor-clearing high avidity T cells. Thus, the development of agents that specifically deplete Treg subsets should translate into more effective immunotherapies while avoiding autoimmunity.
Highlights
Activation, amplification, and survival of CD8+ cytotoxic T lymphocytes (CTL) are required as part of a successful adaptive immune response to developing tumors
These mice were confirmed to express high and low avidity T cell receptors specific for the RNEU420–429 epitope using dilutional tetramer staining of naıve TCR transgenic T cells isolated directly from the TCR transgenic mice (Figure S1), and using ELISpot as a functional analysis of avidity
Comparison of high versus low avidity T cell populations isolated from vaccinated TCR transgenic mice and assessed either directly or following a one week stimulation with the RNEU420–429 peptide, demonstrated that the high avidity T cell populations were better cytokine producers when tested against NT2.5 tumors as targets (Data not shown)
Summary
Activation, amplification, and survival of CD8+ cytotoxic T lymphocytes (CTL) are required as part of a successful adaptive immune response to developing tumors. Multiple mechanisms of peripheral immune tolerance exist that prevent complete activation of CTL, including ignorance, deletion, functional inactivation, and T regulatory cell (Treg)-mediated suppression [1,2,3,4,5,6]. Low avidity CTL specific for the same antigenic epitope exit the thymus but are thought to remain nonfunctional in the periphery, presumably due to inefficient activation and maintenance of function. Due to efficient thymic deletion and peripheral suppression of high avidity T cells, low avidity T cells are the predominant population of T cells available for activation in the periphery of cancer bearing hosts. Cancer vaccines are designed to activate and enhance cancer-antigen-targeted T cells that are suppressed through multiple mechanisms of immune tolerance in cancer-bearing hosts. We developed high and low avidity HER-2/ neu-specific TCR transgenic mouse colonies specific for the same HER-2/neu epitope to define the tolerance mechanisms that affect high versus low avidity tumor-specific T cells
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