Dendritic cells direct circadian anti-tumour immune responses

Abstract

The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance.

Timing of the infusion of nivolumab for patients with recurrent or metastatic squamous cell carcinoma of the esophagus influences its efficacy

“…One of the mechanisms behind this effect is considered to be lymphocyte circadian oscillations. Lymphocyte and dendritic cell homing to lymph nodes occurs in a circadian manner that peaks at the active phase, with cells leaving the tissue during the rest phase [ 15 – 17 ]. Tumor tissue consists not only of cancer cells, but also numerous non-cancer cells, such as fibroblasts, epithelial cells, lymphocytes, macrophages, and myeloid-derived suppressor cells.…”

Neutrophil extracellular traps in tumor progression and immunotherapy

“…Macrophages and Dendritic Cells (DCs), two major Antigen Presenting Cells (APCs), are pivotal innate immune cells that regulate the anti-tumour immune responses ( 116 , 117 ). It has been shown that NETs activate macrophages and DCs through upregulating important costimulatory molecules (CD80, CD86) at early times (30 min), however, macrophages and DCs undergo apoptosis after prolonged incubation with NETs ( 118 ).…”

Molecular crosstalk between circadian clock and cancer and therapeutic implications

“…For example, BMAL1::CLOCK recruits immune-suppressive microglia cells to the TME of glioblastoma (GBM) via transcriptional activation of the OLFML3 gene (38). Circadian expression of the co-stimulatory molecule CD80 in dendritic cells governs a circadian response of tumor antigen-specific CD8+ T cells to melanoma development (39). The CLOCK protein interacts with HIF-1 to activate VEGF expression, facilitating angiogenesis and metastasis in colorectal cancer (40).…”