Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.

Macrophages are prime therapeutic targets due to their pro-tumorigenic and immunosuppressive functions in tumors, but varying efficacy of therapeutic approaches targeting macrophages highlights our incomplete understanding of how the tumor microenvironment (TME) can influence regulation of macrophages. The circadian clock is a key internal regulator of macrophage function, but how circadian rhythms of macrophages may be influenced by the tumor microenvironment remains unknown. We found that conditions associated with the TME such as polarizing stimuli, acidic pH, and elevated lactate concentrations can each alter circadian rhythms in macrophages. Circadian rhythms were enhanced in pro-resolution macrophages but suppressed in pro-inflammatory macrophages, while acidic pH had divergent effects on circadian rhythms depending on macrophage phenotype. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate that pH-driven changes in circadian rhythms are not mediated solely by the cAMP signaling pathway. Remarkably, clock correlation distance analysis of tumor-associated macrophages (TAMs) revealed evidence of circadian disorder in TAMs. This is the first report providing evidence that circadian rhythms of macrophages are altered within the TME. Our data suggest that heterogeneity in circadian rhythms at the population level may underlie this circadian disorder. Finally, we sought to determine how circadian regulation of macrophages impacts tumorigenesis, and found that tumor growth was suppressed when macrophages had a functional circadian clock. Our work demonstrates a novel mechanism by which the tumor microenvironment can influence macrophage biology through altering circadian rhythms, and the contribution of circadian rhythms in macrophages to suppressing tumor growth.

Do macrophages follow the beat of circadian rhythm in TIME (Tumor Immune Microenvironment)?

Advances in cancer research have made clear the critical role of the immune response in clearing tumors. This breakthrough in scientific understanding was heralded by the success of immune checkpoint blockade (ICB) therapies such as anti-programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), as well as the success of chimeric antigen receptor (CAR) T cells in treating liquid tumors. Thus, much effort has been made to further understand the role of the immune response in tumor progression, and how we may target it to treat cancer. Macrophages are a component of the tumor immune microenvironment (TIME) that can promote tumor growth both indirectly, by suppressing T cell responses necessary for tumor killing, as well as directly, through deposition of extracellular matrix and promotion of angiogenesis. Thus, understanding regulation of macrophages within the tumor microenvironment (TME) is key to targeting them for immunotherapy. However, circadian rhythms (24-hour cycles) are a fundamental aspect of macrophage biology that have yet to be investigated for their role in macrophage-mediated suppression of the anti-tumor immune response Circadian rhythms regulate macrophage-mediated immune responses through time-of-day-dependent regulation of macrophage function. A better understanding of the circadian biology of macrophages in the context of the TME may allow us to exploit synergy between existing and upcoming treatments and circadian regulation of immunity.

MYC Ran Up the Clock: The Complex Interplay between MYC and the Molecular Circadian Clock in Cancer.

The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 h) rhythms in most eukaryotic cells and organisms, as a mechanism to adapt to light/dark cycles. Disruption of human circadian rhythms, such as through shift work, may serve as a risk factor for cancer, but connections with oncogenic drivers such as MYC were previously not well understood. In this review, we examine recent evidence that MYC in cancer cells can disrupt the molecular clock; and conversely, that molecular clock disruption in cancer can deregulate and elevate MYC. Since MYC and the molecular clock control many of the same processes, we then consider competition between MYC and the molecular clock in several select aspects of tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, and immune infiltrate in the tumor. Finally, we discuss how the molecular clock can be monitored or diagnosed in human tumors, and how MYC inhibition could potentially restore molecular clock function. Further study of the relationship between the molecular clock and MYC in cancer may reveal previously unsuspected vulnerabilities which could lead to new treatment strategies.