Fortin et al. showed that the circadian clock-mediated crosstalk between epithelial and immune cells in the intestine changes the tumor immune landscape, leading to immunosuppression. Genetic and environmental disruption of the epithelial cell clock resulted in the hyperactivation of pro-inflammatory cytokines and chemokines that promoted heightened inflammation, recruitment of neutrophils, and the subsequent development of MDSCs. PD-L1-expressing MDSCs rhythmically peaked in abundance during the early active phase, and the timing of anti-PD-L1 delivery enhanced treatment efficacy and outcomes in several tumor models.
Contributed by Shishir Pant
ABSTRACT: The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8(+) T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.
Author Info: (1) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (2) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
Author Info: (1) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (2) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (3) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA. (4) Department of Pathology, University of Hail, Hail, Saudi Arabia. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. (5) Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA. (6) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (7) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (8) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (9) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (10) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. (11) Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA. (12) Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. Department of Surgery, Division of Surgical Oncology, University of California Irvine, Orange, CA, USA. (13) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. Department of Medicine, Division of Hematology/Oncology, University of California Irvine, Irvine, CA, USA. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA. (14) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA. (15) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA. (16) Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. (17) Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA. (18) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA. (19) Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. smasri@uci.edu. Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. smasri@uci.edu. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA. smasri@uci.edu.
