Wang Xueling, Li Li, Song Xianqin, Fang Kehua, Chang Xiaotian
Medical Research Center, The Affiliated Hospital of Qingdao University, Wutaishan Road 1677, Qingdao, 266000, People's Republic of China.
Changsha Health Vocational College, Yuening Road 6, Changsha, 410000, People's Republic of China.
Cancer Immunol Immunother. 2025 Jul 12;74(8):263. doi: 10.1007/s00262-025-04044-w.
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.
在许多疾病中都检测到了CD38+自然杀伤细胞（NK细胞）。本研究调查了CD38+NK细胞在肿瘤免疫监视中的机制。通过流式细胞术检测发现，乳腺癌、结直肠癌（CRC）、食管癌、胃癌（GC）、肺癌（LG）或卵巢癌（OC）患者外周血中CD38+NK细胞的比例显著增加。转录组学和代谢组学揭示了CRC中CD38+NK细胞的特殊表达谱和代谢物丰度模式，特别是热休克70 kDa蛋白1A（HSPA1）表达降低和腺苷（ADO）水平升高。与健康个体的CD38+NK细胞相比，CRC的CD38+NK细胞呈现出较低的烟酰胺腺嘌呤二核苷酸（NAD+）生成、凋亡诱导能力和肿瘤细胞杀伤能力，以及更高的肿瘤组织浸润和肿瘤细胞增殖诱导能力。CRC的CD38+NK细胞还产生较少的肿瘤坏死因子-α（TNF-α）和较多的白细胞介素-2（IL-2）、ADO和转化生长因子-β（TGF-β）。当用抗CD38抗体预处理CD38+NK细胞时，得到了相反的结果，且γ干扰素（IFN-γ）生成增加。移植了小鼠结肠肿瘤来源的MC38细胞的野生型C57BL/6 J小鼠，与用CD38基因敲除（KO）小鼠建立的荷瘤模型相比，肿瘤生长更大，外周血中调节性T细胞（Treg）和CD38+NK细胞水平更高，辅助性T细胞1（Th1）水平更低。此外，通过实时聚合酶链反应（PCR）和蛋白质免疫印迹分析检测到CRC的CD38+NK细胞中CD38、程序性死亡受体1（PD-1）和核因子κB（NF-κB）表达增加，而CD16、沉默信息调节因子1（Sirt1）、沉默信息调节因子6（Sirt6）和HSPA1表达降低，这表明NK细胞表达高CD38和低CD16。在CRC、GC、LC和OC患者的血液中检测到高比例的CD38+CD16-NK细胞。众所周知，高Treg、TGF-β、PD-1和ADO水平，以及低HSPA1、NAD+、TNF-α和IFN-γ水平有助于肿瘤细胞免疫逃逸。我们的结果表明，肿瘤患者中高比例的CD38（高）CD16（低）NK细胞会干扰免疫监视并促进肿瘤生长。
