Scientific publications

TCR-induced FOXP3 expression by CD8 + T cells impairs their anti-tumor activity

Mar 1, 2022 | Magazine: Cancer Letters

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


Abstract

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.

CITA DEL ARTÍCULO Cancer Lett. 2022 Mar 1;528:45-58. doi: 10.1016/j.canlet.2021.12.030. Epub 2021 Dec 29.

Our authors

Teresa Lozano Moreda
Silueta investigador
Enrique Conde Gallastegi
Investigadora predoctoral del Programa de Inmunología e Inmunoterapia del Cima Universidad de Navarra
Celia Martín Otal
Flor Navarro Negredo
Aritz Lasarte Cía
Diego Alignani
Senior Research Technician Cytometry Platform
Marta Gorraiz Ayala
Investigador postdoctoral del Grupo de Patología Mieloide del Cima Universidad de Navarra
Juan Pablo Romero Riojas
Sandra Hervás Stubbs
Researcher | Principal Investigator Immunology and Immunotherapy Research Program