Foxp1 Regulates Anti-tumor Effector Functions of CD8+ T cells in Ovarian Cancer (46.46)

Abstract

Abstract T cell based adoptive immunotherapy induces potent anti-tumor response in many cancers. Highly immunosuppressive tumor microenvironment, however, severely impairs effector functions and survival of transferred T cells. In order to gain the best possible immune elimination of tumor cells, specific molecular changes that impair T cell effector functions in the tumor microenvironment need to be identified and targeted. We recently reported that transcription factor Foxp1 critically regulates T cell effector functions as Foxp1-deficient CD8+T cells are better effectors. Here we demonstrate that immunosuppressive tumor microenvironment results in the upregulation of Foxp1 in tumor-reactive T cells, and impairs their effector functions. Consequently, mice bearing ovarian tumors survived significantly longer upon receiving adoptively transferred tumor-primed Foxp1-deficient T cells. In vitro studies further showed that Foxp1-deficient CD8+ T cells can proliferate better in the presence of immunosuppressive TGFb1. Analysis of adoptively transferred T cells showed that, compared to WT CD8+ T cells, Foxp1-deficient CD8+, but not CD4+, T cells survive better in the immunosuppressive tumor microenvironment. Tumor bearing mice receiving Foxp1-deficient effector T cells rejected secondary tumors indicating generation of anti-tumor T cell memory. Our findings indicate that targeting the transcription factor Foxp1 on effector T cells can dramatically improve anti-tumor immunotherapy.