Trafficking of High Avidity HER-2/neu-Specific T Cells into HER-2/neu-Expressing Tumors after Depletion of Effector/Memory-Like Regulatory T Cells

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.

Harnessing the immune system for the treatment of breast cancer

“…This suggests direct crosstalk between the tumor cells and Treg cells. Consistent with the large body of studies showing that Treg cells are strong promoters of breast cancer progression and metastasis, anti-CD25 antibody-mediated Treg blockade or depletion leads to a stronger antitumor immune response and better clinical outcomes (Rech et al, 2012;Weiss et al, 2012). Together, these studies suggest that the Treg cell is a potent negative regulator of anti-tumor immune responses and represents an attractive therapeutic target in breast cancer.…”

Limited Induction of Tumor Cross-Reactive T Cells without a Measurable Clinical Benefit in Early Melanoma Patients Vaccinated with Human Leukocyte Antigen Class I–Modified Peptides

“…In addition, several preclinical studies have shown that Tregs might help to maintain immune tolerance and restrain vaccine-induced tumor immunity by controlling suboptimal rather than high-affinity TCR-bearing T cells (41,42). Together with a recent report on the ability of cyclophosphamide to enhance the trafficking of highavidity CTLs to tumor sites (43), this evidence suggests that cyclophosphamide should favor the expansion of highavidity CTLs in a peptide-vaccine setting. Regarding the use of low-dose IL-2, we deliberately chose the "late" administration schedule (i.e., 3 months after the beginning of vaccination) based on a previous report by Slingluff and colleagues that showed a beneficial effect with such a schedule compared with that of early IL-2 administration for the induction of T-cell responses by a multipeptide melanoma vaccine (16).…”

Effects of Gastric Cancer Cells on the Differentiation of Treg Cells

“…Patients and experimental models with cancer showed that Treg cells down-regulated the activity of effector function against tumors, resulting in T-cell dysfunction in cancerbearing hosts (Weiss et al, 2012;Sakuishi et al, 2013). An increased population of Treg cells was reported in patients with ovarian cancer (Wicherek et al, 2011), lung cancer (Erfani et al, 2012), and breast cancer (Decker et al, 2012).…”