Sirtuin 6 is a negative regulator of the anti-tumor function of natural killer cells in murine inflammatory colorectal cancer

Colorectal cancer (CRC) is the world’s third most commonly diagnosed and second most fatal cancer (Hossain et al., 2022). The immune system plays a significant role in the surveillance and control of CRC development (Mezheyeuski et al., 2021, Kather and Halama, 2019). Immune cells participating in CRC immunity include natural killer (NK) cells, CD4+ T cells, CD8+ cytotoxic T cells, B cells, macrophages, and dendritic cells (Kather and Halama, 2019, Guo et al., 2020). Notably, NK cells are potent tumoricidal cells. Upon encountering malignant cells, an array of surface molecules on NK cells elicit activating or inhibitory signals to modulate NK cells to release cytotoxic mediators such as perforin and granzymes (Wu et al., 2020). NK cells, either circulating or intratumoral, are reported as a favorable prognostic marker in CRC (Tang et al., 2020, Coca et al., 1997, Donadon et al., 2017). In a rat CRC model, follicle-like NK cell aggregates were found to be localized in the tunica mucosa and tunica submucosa of colorectal tumors, suggesting their role in fighting CRC development (Bahr et al., 2021). NK cell-based immunotherapy has been regarded as a promising option for CRC treatment. However, CRC-associated NK cell exhaustion impairs NK cell tumoricidal capacity especially in the local CRC tissue to incur immune escape of CRC (Sorrentino et al., 2021, Rocca et al., 2016, Rocca et al., 2013). NK cells exhibited multiple phenotypic changes and a profound down-regulation of NK cell-activating receptors in CRC patients (Rocca et al., 2013). Therefore, NK cell exhaustion or dysfunction may severely reduce the efficiency of NK cell-based immunotherapy against CRC. Unfortunately, the factors resulting in CRC-associated NK cell exhaustion, either intrinsic or extrinsic, have not been completely understood.

Sirtuin 6 (SIRT6) belongs to the Sirtuin family of NAD-dependent enzymes that modulate cellular stress response, genome stability, aging, and metabolism (Korotkov et al., 2021). Localized to the nucleus, the ADP-ribosyl transferase and histone deacetylase activities of SIRT6 make it essential for DNA repair, maintenance of telomeric chromatin, inflammation, lipid and glucose metabolism (Chang et al., 2020). SIRT6 deacetylates histone H3 lysine 9 (H3K9), H3K18, and H3K56 to induce transcriptional repression (Pillai and Gupta, 2021). SIRT6 is also implicated in transcriptional repression independently of its deacetylase activity (Etchegaray et al., 2019, Ravi et al., 2019). Recent studies imply that SIRT6 could be a master regulator of immune function. High SIRT6 expression is observed in immune organs including the spleen, lymph node, and bone marrow, as well as immune cells including white blood cells (Pillai and Gupta, 2021). Indeed, SIRT6 has been implicated in the regulation of neutrophil and macrophage activities (Lee et al., 2013, Koo et al., 2019). Nonetheless, little is known about the role of SIRT6 in NK cell functionality.

In this research using a murine CRC model, we characterized the expression and function of SIRT6 in NK cells. We found that SIRT6 was up-regulated in exhausted infiltrating NK cells in the murine CRC tissue. SIRT6 knockdown promoted NK cell cytotoxicity both in vitro and in vivo, suggesting SIRT6 is a negative regulator in murine NK cells. Therefore, we discovered a novel molecular factor essential for NK cell exhaustion in murine CRC.

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