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Natural killer (NK) cells inhibit colorectal carcinoma (CRC) initiation and progression through their tumoricidal activity. However, cumulative evidence suggests that NK cells become functionally exhausted in patients with CRC. To deepen the understanding of the mechanisms underlying CRC‐associated NK cell exhaustion, we explored the expression and effect of Sirtuin 2 (Sirt2) in mesenteric lymph node (mLN) NK cells in a murine colitis‐associated CRC model. Sirt2 was remarkably up‐regulated in mLN NK cells after CRC induction. Particularly, Sirt2 was increased in mLN NK cells expressing high T cell immunoglobulin and mucin domain‐3 (TIM3), high lymphocyte activation protein‐3 (LAG3), high programmed death‐1 (PD‐1), high T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), high NK group 2 member A (NKG2A), but low tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL), low interferon‐gamma and low granzyme B. In addition, Sirt2 was also increased in NK cells after induction of exhaustion in vitro. Lentivirus‐mediated Sirt2 silencing did not affect the acute activation and cytotoxicity of non‐exhausted NK cells. However, Sirt2 silencing partially restored the expression of interferon‐gamma, granzyme B and CD107a in exhausted NK cells. Meanwhile, Sirt2 silencing down‐regulated TIM3, LAG3, TIGIT and NKG2A while up‐regulated TRAIL on exhausted NK cells. Consequently, Sirt2 silencing restored the cytotoxicity of exhausted NK cells. Moreover, Sirt2 silencing partially ameliorates the defects in glycolysis and mitochondrial respiration of exhausted NK cells, as evidenced by increases in glycolytic capacity, glycolytic reserve, basal respiration, maximal respiration and spare respiration capacity. Accordingly, Sirt2 negatively regulates the tumoricidal activity of exhausted NK cells in CRC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the world's leading cause of tumor‐related mortalities. Natural killer (NK) cells play a critical role at the first immunological defense line against HCC initiation and progression. NK cell dysfunction is therefore an important mechanism for immune evasion of HCC cells. In the present study using a murine HCC model, we revealed the down‐regulation of PR/SET Domain 10 (PRDM10) in hepatic NK cells that were phenotypically and functionally exhausted. PRDM10 silencing diminished the expression of natural killer group 2 member D (NKG2D) and tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL), augmented T cell immunoglobulin and ITIM domain (TIGIT) expression, and decreased the expression of interferon (IFN)‐γ, perforin and granzyme B in normal hepatic NK cells in vitro. Consistently, PRDM10‐deficient NK cells exhibited impaired cytotoxicity on target cells. In contrast, PRDM10 over‐expression promoted NKG2D and Fas ligand (FasL) expression, reduced CD96 expression and enhanced transcripts of IFN‐γ, perforin and granzyme B in NK cells in vivo. Moreover, PRDM10 silencing and PRDM10 over‐expression down‐regulated and up‐regulated Eomesodermin (Eomes) expression, respectively. In summary, this study reveals PRDM10 down‐regulation as a novel mechanism underlying NK cell dysfunction and identifies PRDM10 as a supporting factor of NK cell function. [ABSTRACT FROM AUTHOR]