Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy

Abstract

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8⁺ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.

Keywords: BMAL1; CAR T therapy; PD-1; chronotherapy; circadian; immune checkpoint blockade; immunology; melanoma; tumor-infiltrating leukocyte.