CD38 modulates cytokine secretion by NK cells through the Sirt1/NF-κB pathway, suppressing immune surveillance in colorectal cancer.

Tregs and M2-type macrophages are essential for immune surveillance. CD38 + NK cells are involved in immunoregulation by modulating cytokine secretion. This study investigated how CD38 + NKs affect Tregs and macrophages in colorectal cancer (CRC). Higher proportions of CD38 + NKs and Tregs were detected in bloods and tumor tissues of CRC patients than that in the samples from healthy controls (HCs). Compared with CD38 + NKs from HCs, the NK cells from CRC promoted the differentiation of Tregs from CD4 + T cells, and secreted increased levels of IL-10, TGF-β and TNF-α and decreased levels of IFN-γ. CD38 + NKs from CRC expressed higher levels of CD38, NF-κB and acetyl-NF-κB and lower levels of Sirt1. When CRC CD38 + NK cells were treated with anti-CD38 monoclonal antibody, the above trends were reversed. CRC CD38 + NKs with treatment of NF-κB inhibitor also showed opposite effects on cytokine secretion and CD4 + T-cell differentiation. After treatment with a Sirt1 activator, NF-κB signaling was inhibited in these CD38 + NKs, whereas treatment with a Sirt1 inhibitor activated NF-κB signaling. The supernatants of CRC CD38 + NK culture promoted M0 macrophage polarization to M2-type. We suggest that CD38 modulates cytokine secretion by NK cells through Sirt1/NF-κB signaling pathway, thereby suppressing immune surveillance in tumorigenesis.