PO.CL05.06 · 临床研究
手术诱导的髓源性抑制细胞扩增和细胞毒性淋巴细胞功能丧失可预测胰腺癌的不良生存
Surgery-induced expansion of myeloid-derived suppressor cells and loss of cytotoxic lymphocyte function predict poor survival in pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺癌仍是一种高度致命的恶性肿瘤，即使在根治性切除后复发率也很高。有证据表明，手术应激会触发炎症和免疫抑制，可能促进肿瘤复发。髓源性抑制细胞（MDSCs）和功能失调的自然杀伤（NK）细胞是这一过程的介导者。我们假设，由NOX2来源的活性氧驱动的手术诱导免疫失调会损害免疫并恶化结局。
从入组IPEP试验（伦理编号057-18）的33例胰腺癌患者中，于术前和术后（第1天和第3-5天）采集外周血单个核细胞。采用单细胞多组学分析（BD Rhapsody）对免疫细胞群和激活状态进行表征。对免疫细胞频率和表面受体表达进行纵向分析，并与患者结局相关联。
对445,152个细胞的分析揭示了循环白细胞在术后的重大变化（表1）。NOX2+单核细胞型MDSCs（M-MDSCs）在术后第1天显著扩增，并在第3-5天持续升高。相反，细胞毒性T细胞和NK细胞在手术后显著减少，术后NK细胞表现出激活受体NKp30表达降低。术后M-MDSC频率高与较差的总生存相关（P = 0.017，n=29，log-rank检验）。
胰腺癌手术诱导以M-MDSC扩增和细胞毒性淋巴细胞抑制为特征的深刻免疫重塑。这些变化与不良结局相关，提示术后免疫功能障碍可能促进复发。靶向NOX2依赖性免疫抑制通路可能有助于保存抗肿瘤免疫并改善术后生存。
1 均值 ± SD 2 CLR标准化蛋白表达的中位数 3 采用Šídák校正的混合效应模型。P值与术前比较。
表1. 健康供者和胰腺癌患者围手术期免疫细胞亚群。健康供者（n=13） 术前（n=33） 术后第1天（n=29）3 术后第3-5天（n=29）3 M-MDSC（占所有细胞%）1 0.3 ± 0.6 2.7 ± 3.3 23.3 ± 12.6（P < 0.0001） 20.2 ± 12.2（P < 0.0001） CD8+ T细胞（占所有细胞%）1 16.5 ± 12.1 20.5 ± 17.5 14.8 ± 14.5（P < 0.01） 14.9 ± 12.3（P < 0.05） NK细胞（占所有细胞%）1 18.9 ± 12.3 14.2 ± 10.5 6.3 ± 7.4（P < 0.001） 7.9 ± 6.6（P < 0.001） NK细胞上的NKp30 2 1 0.4 ± 0.2 0.5 ± 0.2 0.3 ± 0.2（P < 0.001） 0.4 ± 0.2
查看英文原文 English abstract
Pancreatic cancer remains a highly lethal malignancy, with high recurrence rates even after curative-intent resection. Evidence suggests that surgical stress triggers inflammation and immunosuppression, potentially facilitating tumor recurrence. Myeloid-derived suppressor cells (MDSCs) and dysfunctional natural killer (NK) cells are mediators of this process. We hypothesized that surgery-induced immune dysregulation, driven by NOX2-derived reactive oxygen species, impairs immunity and worsens outcomes.
Peripheral blood mononuclear cells from 33 pancreatic cancer patients enrolled in the IPEP trial (ethical no. 057-18) were collected pre- and postoperatively (days 1 and 3-5). Single-cell multiomic profiling (BD Rhapsody) was used to characterize immune populations and activation. Frequencies of immune cells and surface receptor expression were analyzed longitudinally and correlated with patient outcome.
Analysis of 445,152 cells revealed major postoperative shifts in circulating leukocytes (Table 1). NOX2 + monocytic MDSCs (M-MDSCs) expanded markedly on postoperative day 1 and remained elevated through day 3-5. Conversely, cytotoxic T and NK cells significantly declined after surgery, and postoperative NK cells showed reduced expression of the activating receptor NKp30. High postoperative M-MDSC frequencies were associated with poorer overall survival (P = 0.017, n=29, log-rank test).
Pancreatic cancer surgery induces profound immune remodeling characterized by M-MDSC expansion and cytotoxic lymphocyte suppression. These changes associate with adverse outcomes, suggesting that postoperative immune dysfunction may promote recurrence. Targeting NOX2-dependent immunosuppressive pathways may help preserve antitumor immunity and improve postoperative survival.
1 Mean ± SD 2 Median CLR-normalized protein expression 3 Mixed-effects model with Šídák correction. P values compared with pre-op.
Table 1. Perioperative immune cell subsets in healthy donors and pancreatic cancer patients. Healthy donor (n=13) Pre-op. (n=33) Post-op. day 1 (n=29) 3 Post-op. day 3-5 (n=29) 3 M-MDSC (% of all cells) 1 0.3 ± 0.6 2.7 ± 3.3 23.3 ± 12.6 ( P < 0.0001) 20.2 ± 12.2 ( P < 0.0001) CD8 + T cells (% of all cells) 1 16.5 ± 12.1 20.5 ± 17.5 14.8 ± 14.5 ( P < 0.01) 14.9 ± 12.3 ( P < 0.05) NK cells (% of all cells) 1 18.9 ± 12.3 14.2 ± 10.5 6.3 ± 7.4 ( P < 0.001) 7.9 ± 6.6 ( P < 0.001) NKp30 2 on NK cells 1 0.4 ± 0.2 0.5 ± 0.2 0.3 ± 0.2 ( P < 0.001) 0.4 ± 0.2
利益披露 Disclosure
O. Johnsson, None..
M. S. Nilsson, None..
R. Kiffin, None..
J. Bourghardt Fagman, None..
C. Vilhav, None..
S. Bratlie, None..
P. L. Naredi, None..
K. Hellstrand, None..
A. Martner, None.