PO.IM02.03 · 免疫学
神经降压素抑制抗肿瘤免疫并与结直肠癌的不良预后相关
Neurotensin suppresses anti-tumor immunity and is associated with poor prognosis in colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言。结直肠癌（CRC）是全球癌症相关死亡的主要原因之一，患者结局存在显著异质性。神经降压素（NTS）及其高亲和力受体（NTSR1）已被认为参与CRC进展，特别是在调节肿瘤代谢和免疫应答方面。NTS的分泌在心理应激和高脂摄入下增加。鉴于NTSR1在免疫细胞上的广泛表达，我们假设NTS调节CRC中的抗肿瘤免疫。本研究的目的是整合临床、体内和功能证据，以阐明NTS对免疫应答和患者结局的影响。
方法。(i) 临床生存：在一个单中心CRC队列（肯塔基大学；n=196）中，按肿瘤NTS表达进行分层分析总生存期（OS），并使用KMplot（n=1,061）进行验证。(ii) 转录组相关性：利用公开数据集（GEPIA/TCGA）评估NTS与免疫抑制基因（如IL10、ENTPD1）之间的相关性。(iii) 体内：将鼠源CRC细胞（MC38）皮下植入NTS野生型（NTSWT）和NTS敲除（NTSKO）小鼠以比较肿瘤生长。通过免疫组织化学（IHC）和流式细胞术定量肿瘤浸润免疫细胞和颗粒酶B（GZMB）表达。(iv) 体外细胞毒性：将MC38细胞与来自MC38致敏小鼠的脾源性CD8+ T细胞共培养，加或不加NTS处理，并通过LDH释放测定细胞毒性。
结果。(i) 高NTS表达在本机构队列中与更短的OS相关（P<0.05），并在KMplot数据集中得到验证（n=1,061；P<0.001）。(ii) NTS表达与多个免疫抑制基因显示出显著正相关，包括IL10（P=0.0038）和ENTPD1（P=0.046）。(iii) 体内，NTSKO小鼠表现出明显更慢的肿瘤生长，免疫细胞浸润增加，瘤内GZMB表达更高。(iv) 体外，NTS处理显著降低了CD8+ T细胞对MC38细胞的细胞毒性，表现为LDH释放减少，支持NTS对效应T细胞功能的直接抑制作用。
结论。高NTS表达可识别预后较差的CRC患者，并通过限制CD8+ T细胞浸润和细胞毒活性在功能上抑制抗肿瘤免疫。降低NTS的干预措施（如减压和饮食优化）可能改善对免疫治疗的应答和临床结局。这些发现为将NTS/NTSR1轴作为靶点联合免疫治疗策略提供了生物学依据。
查看英文原文 English abstract
Introduction. Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide with substantial heterogeneity in patient outcomes. Neurotensin (NTS) and its high-affinity receptor (NTSR1) have been implicated in CRC progression, particularly in modulating tumor metabolism and immune responses. NTS secretion increases under psychological stress and high-fat intake. Given the widespread expression of NTSR1 on immune cells, we hypothesized that NTS modulates anti-tumor immunity in CRC. The purpose of our current study was to integrate clinical, in vivo , and functional evidence to delineate the impact of NTS on immune responses and patient outcomes.
Methods. (i) Clinical survival: Overall survival (OS) was analyzed in a single-institution CRC cohort (University of Kentucky; n=196) stratified by tumor NTS expression, and findings were validated using KMplot (n=1,061). (ii) Transcriptomic correlation: Correlations between NTS and immunosuppressive genes (e.g., IL10, ENTPD1) were assessed utilizing publicly available datasets (GEPIA/TCGA). (iii) In vivo : Murine CRC cells (MC38) were implanted subcutaneously into NTS wild-type (NTSWT) and NTS knockout (NTSKO) mice to compare tumor growth. Tumor-infiltrating immune cells and granzyme B (GZMB) expression were quantified by immunohistochemistry (IHC) and flow cytometry. (iv) In vitro cytotoxicity: MC38 cells were co-cultured with spleen-derived CD8+ T cells from MC38-primed mice, with or without NTS treatment, and cytotoxicity was measured by LDH release.
Results. (i) High NTS expression was associated with shorter OS in the institutional cohort (P<0.05) and was validated in the KMplot dataset (n=1,061; P<0.001). (ii) NTS expression showed significant positive correlations with multiple immunosuppressive genes, including IL10 (P=0.0038) and ENTPD1 (P=0.046). (iii) In vivo , NTSKO mice exhibited markedly slower tumor growth, with increased immune-cell infiltration and higher intratumoral GZMB expression. (iv) In vitro , NTS treatment significantly reduced CD8+ T-cell cytotoxicity against MC38 cells, as indicated by decreased LDH release, supporting a direct suppressive effect of NTS on effector T-cell function.
Conclusions. High NTS expression identifies CRC patients with poorer prognosis and functionally suppresses anti-tumor immunity by limiting CD8+ T-cell infiltration and cytotoxic activity. Interventions that lower NTS (e.g., stress reduction and dietary optimization) may improve responses to immunotherapy and clinical outcomes. These findings provide a biological rationale for targeting the NTS/NTSR1 axis in combination with immunotherapeutic strategies.
利益披露 Disclosure
H. Wu, None..
Y. Wang, None..
D. Napier, None..
H. Jiang, None..
D. Li, None..
J. Li, None..
B. Evers, None.