A high proportion of CD38 (high) CD16 (low) NK cells in colorectal cancer can interrupt immune surveillance and favor tumor growth.

Abstract

CD38 + NK cells have been detected in many diseases. The present study investigated the mechanism of CD38 + NK cells in immune surveillance in tumors. Significant increases in the proportions of CD38 + NK cells were detected via flow cytometry in the peripheral blood of patients with breast cancer, colorectal cancer (CRC), esophageal cancer, gastric cancer (GC), lung cancer (LG) or ovarian cancer (OC). Transcriptomics and metabonomics revealed special expression profiles and metabolite abundance patterns in CRC CD38 + NK cells, especially decreased HSPA1 (heat shock 70 kDa protein 1A) and increased ADO (adenosine) levels. Compared with CD38 + NK cells from healthy individuals, CRC CD38 + NK cells presented lower NAD + (nicotinamide adenine dinucleotide) production, apoptosis-inducing ability and tumor cell killing ability, and higher infiltration into tumor tissues and tumor cell proliferation-inducing ability. CRC CD38 + NK cells also produce less TNF-alpha and more IL-2, ADO and TGF-beta. When the CD38 + NK cells were pretreated with anti-CD38 antibodies, the opposite results were obtained, and IFN-gamma production was increased. Wild-type C57BL/6 J mice grafted with mouse colon tumor-derived MC38 cells presented greater tumor growth, as well as higher Treg and CD38 + NK cell levels and lower Th1 cell levels in the peripheral blood than did the tumor-bearing model established with CD38 KO mice. Additionally, increased CD38, PD-1 and NF-kB expression and decreased CD16, Sirt1, Sirt6 and HSPA1 expression were detected in CRC CD38 + NK cells via real-time PCR and Western blot analysis, indicating that the NK cells expressed high CD38 and low CD16. High proportions of CD38 + CD16- NK cells were detected in the blood of CRC, GC, LC and OC patients. It is well known that high Tregs, TGF-beta, PD-1 and ADO levels, and low HSPA1, NAD + , TNF-alpha and IFN-gamma levels contribute to immune tumor cell escape. Our results suggest that a high proportion of CD38 (high) CD16 (low) NK cells in tumor patients can interrupt immune surveillance and favor tumor growth.