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Circadian Control of Tumor Immunosuppression Impacts Efficacy of Immune Checkpoint Blockade

ABSTRACT: The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation plays an essential role in host defense as well as tumor immunosurveillance. Using a single cell RNA-sequencing approach in a genetic model of colorectal cancer (CRC), we identified clock-dependent changes to the immune landscape that dictate 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. Mechanistically, we identified that disruption of the epithelial cell clock regulates the secretion of cytokines and chemokines that promote heightened inflammation, recruitment of neutrophils, and the subsequent development of MDSCs. We leveraged these findings to demonstrate that time-of-day delivery of anti-PD-L1 immunotherapy is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, our results indicate that circadian gating of tumor immunosuppression informs the timing and optimal efficacy of immune checkpoint inhibitors (ICIs).

ORGANISM(S): Mus musculus

PROVIDER: GSE262267 | GEO | 2024/04/22

REPOSITORIES: GEO

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Project description:Background: The disruption of the circadian clock is associated with inflammatory and immunological disorders. BMAL2, a critical circadian protein, forms a dimer with CLOCK, activating transcription. Extracellular cold-inducible RNA-binding protein (eCIRP), released during sepsis, can induce macrophage endotoxin tolerance. We hypothesized that eCIRP modulates BMAL2 expression and promotes macrophage endotoxin tolerance through triggering receptor expressed on myeloid cells-1 (TREM-1). Methods: C57BL/6 wild-type (WT) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Serum was collected 20 hours post-CLP to assess eCIRP levels. Peritoneal macrophages (PerM) and immortalized bone marrow-derived macrophages (iBMDMs) were seeded into plates and treated with recombinant mouse (rm) CIRP (eCIRP) at various doses. Induction of BMAL2 activation in iBMDM was performed by transfection of BMAL2 CRISPR activation plasmid. Circadian gene expression profiles in eCIRP-treated macrophages were determined by PCR array and confirmed by qPCR. Cytokine levels in the culture supernatants were assessed by ELISA. The interaction of BMAL2 in the PD-L1 promoter was determined by computational modeling and confirmed by the BIAcore assay. Results: PCR array screening of circadian clock genes in peritoneal macrophages treated with eCIRP revealed the elevated expression of BMAL2, CRY1, and PER2. eCIRP serum levels were increased in septic mice. In eCIRP-treated macrophages, TREM-1 deficiency prevented the upregulation of these circadian genes. Macrophages pre-treated with eCIRP exhibited reduced TNFá and IL-6 release upon LPS challenge, indicating macrophage endotoxin tolerance. In addition, eCIRP increased the expression of PD-L1, IL-10, and STAT3, markers of immune tolerance. Interestingly, TREM-1 deficiency reversed eCIRP-induced macrophage endotoxin tolerance. In macrophages, inducible BMAL2 expression correlated with increased PD-L1 expression. In septic human patients, blood monocytes exhibited increased expression of BMAL2 and PD-L1 in comparison to healthy subjects. Computational modeling and BIAcore assay identified a putative binding region of BMAL2 in the PD-L1 promoter, suggesting BMAL2 positively regulates PD-L1 expression in macrophages. Conclusion: eCIRP upregulates BMAL2 expression via TREM-1, leading to macrophage endotoxin tolerance in sepsis. Targeting eCIRP to maintain circadian rhythm may correct endotoxin tolerance and enhance host resistance to bacterial infection.

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Circadian Control of Tumor Immunosuppression Impacts Efficacy of Immune Checkpoint Blockade

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