TCR-induced FOXP3 expression by CD8 + T cells impairs their anti-tumor activity
Teresa Lozano 1, Enrique Conde 2, Celia Martín-Otal 2, Flor Navarro 2, Aritz Lasarte-Cia 2, Rabab Nasrallah 3, Diego Alignani 4, Marta Gorraiz 2, Pablo Sarobe 2, Juan P Romero 5, Amaia Vilas 5, Rahul Roychoudhuri 6, Sandra Hervás-Stubbs 2, Noelia Casares 2, Juan José Lasarte 7
Adoptive cell transfer therapy using CD8+ T lymphocytes showed promising results eradicating metastatic malignancies. However, several regulatory mechanisms limit its efficacy. We studied the role of the expression of the transcription factor FOXP3 on CD8+ T cell function and anti-tumor immunity. Here we show that suboptimal T cell receptor stimulation of CD8+ T cells upregulates FOXP3 in vitro.
Similarly, CD8 T cells transferred into tumor-bearing mice upregulate FOXP3 in vivo. Cell-intrinsic loss of FOXP3 by CD8+ T cells resulted in improved functionality after TCR stimulation and better antitumor responses in vivo. Inhibition of the FOXP3/NFAT interaction likewise improved CD8+ T cell functionality.
Transcriptomic analysis of cells after TCR stimulation revealed an enrichment of genes implicated in the response to IFN-γ, IFN-α, inflammatory response, IL-6/JAK/STAT, G2M checkpoint, and IL-2/STAT signaling in FOXP3-deficient CD8+ T cells with respect to FOXP3-wt CD8+ T cells.
Our results suggest that transient expression of FOXP3 by CD8+ T cells in the tumor microenvironment restrains their anti-tumor activity, with clear implications for improving T cell responses during immunotherapy.
Keywords: Adoptive cell therapy; CD8(+) T cells; FOXP3; NFAT.