Physiological activation of Aryl hydrocarbon receptor by food-derived ligands is essential for the efficacy of anti-PD1 therapy

Abstract

Cancer immuno-surveillance and response to therapy are affected by environmental factors, including nutrition. However, the direct effects of individual nutrients remain poorly understood. Here we investigate the impact of dietary ligands of Aryl hydrocarbon receptor (AhR), a transcription factor activated by tryptophan catabolites generated through food digestion and microbiota metabolism. By analyzing pre-clinical tumor models in mice fed on a diet naturally poor in AhR ligands or the same diet supplemented with Indole-3-carbinol, we show that diet-derived AhR ligands are required for the optimal efficacy of anti-PD1 therapy. Using conditional knockout mice, we evidence an essential role for AhR in CD8 T cells, but not NK cells or myeloid cells. Mechanistically, AhR promotes anti-PD1-mediated reinvigoration of progenitor exhausted CD8 T cells and licences the functional response of effector CD8 T cells. Our work allows a better understanding of the role of nutrients in anti-tumor immune responses and has implications for the rational design of dietary interventions for improving the efficacy of checkpoint blockade therapy.