Abstract 2702: Contribution of effector regulatory T cells to the regulation of antitumor immunity

Abstract

Abstract Regulatory T cells (Treg) belonging to the FoxP3 lineage stringently control immune responses and self-tolerance. Follicular regulatory T (TFR) cells, an effector Treg (eTreg) subset, not only suppress cellular responses but also regulate the magnitude and quality of the germinal center (GC)-antibody (Ab) response through interactions with activated follicular helper T (TFH) cells and GC B cells. Although the Blimp1 transcription factor has been used as a phenotypic marker for eTreg, its contribution to the lineage stability and suppressive activity of eTreg, particularly TFR, has been clouded in uncertainty. In contrast to the current view that Blimp1 may have a negative impact on the TFR response, our recent analysis of mice that harbor a FoxP3-specific deletion of Blimp1 has shown that expression of Blimp1 in eTreg (including TFR) is essential for the maintenance of FoxP3 expression and stable eTreg suppressive phenotype. We then generated B16 melanoma model in these mice and investigated the impact of Blimp1 deficient eTreg on the tumorigenesis. These mice had delayed tumor growth compared to WT controls. The enhanced antitumor immunity in mice with Blimp1 deficient eTreg reflected reprogramming of unstable eTreg into T-cells with effector activity (Teff) specifically within the tumor and loss of suppression on TFH-Ab responses, leading to intratumoral TFH expansion, Ab deposition and enhanced CD8+ T-cell and NK cell effector function. Further analysis of mice expressing a conditional and tamoxifen-inducible Blimp1 deletion within the FoxP3+ lineage revealed the specific contribution of Blimp1 deficient TFR cells to antitumor immune response. These results suggest that induction of eTreg lineage instability provokes intratumoral eTreg conversion into Teff −a new source of effector activity by T-cells within the tumor and enhances robust Ab responses. The increased cellular and humoral responses cooperatively promote antitumor immunity. Insights from our studies may suggest new approaches to manipulate eTreg for better vaccines or combined immunotherapeutic approaches to melanoma or other types of cancer. Citation Format: Michael L. Dixon, Lin Luo, Jianmei W. Leavenworth. Contribution of effector regulatory T cells to the regulation of antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2702.