180P - Chronic circadian disruption promotes melanoma progression by interfering with NK cells

Background

Circadian rhythms (CRs) are crucial biological processes that influence various physiological functions in humans. Previous studies from our team have shown that chronic circadian disruption, specifically chronic jetlag (CJL), increases tumor burden in a mouse melanoma model. The tumor immune microenvironment plays a complex regulatory role in tumorigenesis. However, the specific immune cell functions regulated by circadian disruption to promote tumor progression remain largely undefined. This study aims to demonstrate the critical role of NK cells in the innate immune system during circadian disruption across various mouse models.

Methods

We utilized three distinct mouse models representing varying immune states: C57BL/6 mice, NOD-SCID mice (lacking T/B cells), and B-NDG mice (lacking T/B/NK cells), melanomas were inoculated subcutaneously. Light was manipulated to modulate the circadian clock. Mice were maintained under normal light-dark environment (LD) or CJL environment (6-hour advance of the LD12:12 cycle every 2 days). We use RNA-seq, flow cytometry and quantitative immunofluorescence to analysis tumor immune microenvironment.

Results

Our findings indicate that tumor growth rates significantly increased under CJL in C57 and NOD-SCID mice compared to normal light-dark schedules. In contrast, the tumor growth rate difference between the two rhythm patterns disappeared in NK-cell-deficient B-NDG mice. Flow cytometry analysis revealed that in C57 mice, CJL led to an increase in CD8+ T cells and a decrease in NK cells in tumors, with similar trends observed in the spleen. Additionally, RNA-seq data indicated that CJL inhibits pathways related to both innate and adaptive immunity in tumors, significantly downregulating NK cell function pathways.

Conclusions

These data demonstrate that chronic circadian disruption promotes tumor progression by altering the tumor immune microenvironment, with changes in NK cell quantity and function playing a pivotal role in CJL's effects on tumor growth.

Legal entity responsible for the study

West China Hospital, Sichuan University.

Funding

Sichuan Science and Technology Program.

Disclosure

All authors have declared no conflicts of interest.