宫颈癌微环境TOX信号通路诱导T细胞耗竭介导的免疫逃逸机制

刘丹; 张谷香; 谢丹; 徐艳; 谢诚芳; 唐雨曦

doi:10.19401/j.cnki.1007-3639.2025.07.007

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宫颈癌微环境TOX信号通路诱导T细胞耗竭介导的免疫逃逸机制

论著 | 更新时间：2025-12-31

- 宫颈癌微环境TOX信号通路诱导T细胞耗竭介导的免疫逃逸机制
- Mechanism of immune escape mediated by T cell depletion induced by TOX signaling pathway in cervical cancer microenvironment
- 中国癌症杂志 2025年35卷第7期页码：685-694
- 作者机构：
  
  长沙市第四医院（长沙市中西医结合医院，湖南师范大学附属长沙医院）妇产科，湖南长沙 410203
- 作者简介：
  
  [ "刘丹（ORCID: 0009-0005-6974-2488），硕士，主治医师。" ]
  张谷香，学士，主任医师。
- 基金信息：
  
  湖南省卫生健康委科研课题计划项目(D20230217951)
- DOI：10.19401/j.cnki.1007-3639.2025.07.007
  中图分类号： R737.33
- 收稿：2024-10-23，
  
  修回：2025-02-06，
  
  纸质出版：2025-07-30
- 稿件说明：
移动端阅览
刘丹, 张谷香, 谢丹, 等. 宫颈癌微环境TOX信号通路诱导T细胞耗竭介导的免疫逃逸机制[J]. 中国癌症杂志, 2025,35(7):685-694.

Dan LIU, Guxiang ZHANG, Dan XIE, et al. Mechanism of immune escape mediated by T cell depletion induced by TOX signaling pathway in cervical cancer microenvironment[J]. China Oncology, 2025, 35(7): 685-694.
刘丹, 张谷香, 谢丹, 等. 宫颈癌微环境TOX信号通路诱导T细胞耗竭介导的免疫逃逸机制[J]. 中国癌症杂志, 2025,35(7):685-694. DOI： 10.19401/j.cnki.1007-3639.2025.07.007.

Dan LIU, Guxiang ZHANG, Dan XIE, et al. Mechanism of immune escape mediated by T cell depletion induced by TOX signaling pathway in cervical cancer microenvironment[J]. China Oncology, 2025, 35(7): 685-694. DOI： 10.19401/j.cnki.1007-3639.2025.07.007.

摘要

背景与目的：

免疫检查点阻断（immune checkpoint blockade，ICB）已成为宫颈癌（cervical cancer，CC）治疗领域有前景的新治疗策略，但终末T细胞耗竭仍然会限制ICB的疗效。分选连接蛋白-9（sorting nexin-9，SNX9）的缺失能够抑制胸腺细胞选择相关高迁移率族盒蛋白（thymocyte selection-associated high mobility group box protein，TOX）缓解T细胞的耗竭，为预防T细胞耗竭和增强癌症免疫治疗效果提供了新思路。因此，本研究旨在探讨CC微环境中的SNX9/TOX信号通路诱导CD8

T细胞耗竭介导的免疫逃逸机制。

方法：

共收集54份外周血样品，其中18份来自CC患者，18份来自高级别鳞状上皮内病变（high-grade squamous intraepithelial lesion，HSIL）患者，18份来自宫颈正常的受试者。此外，研究收集了在本院进行初次手术的153对CC及癌旁组织。从医院记录中获得CC患者的临床病理学特征、肿瘤分期、随访记录和其他相关临床病理学数据。本研究经长沙市第四医院伦理委员会批准（审批号：20220206）。24只小鼠随机分配到免疫球蛋白G（immunoglobulin G，IgG）组、Anti-SNX9组、Anti-程序性死亡蛋白-1（programmed death-1，PD-1）组和Anti-SNX9

Anti-PD-1组，每组6只。各组分别接受腹膜内注射封闭抗体和同型对照治疗。通过ELISpot检测CD8

T细胞分泌肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）和γ干扰素（interferon-γ，IFN-γ）的能力。采用蛋白质印迹法（Western blot）、免疫组织化学检测CC组织中TOX和SNX9的表达。

结果：

CC患者的外周血单个核细胞（peripheral blood mononuclear cell，PBMC）中SNX9、TOX mRNA的表达明显高于HSIL和正常对照（

0.05）。CC组织中SNX9的阳性细胞水平、TOX免疫组织化学评分较癌旁组织显著提高（

=18.63、21.10，

0.001）。SNX9在CC中的高表达与低分化/未分化、肿瘤大小、宫旁浸润、阴道浸润、晚期FIGO分期及盆腔淋巴结转移相关（

0.05）。与SNX9低表达组相比，SNX9高表达组CC患者手术后的总生存期较短（

0.05）。CC患者的CD8

SNX9

T细胞的比例明显高于正常对照和HSIL患者（

0.05）。CD8

SNX9

T细胞分泌细胞因子（TNF-α和IFN-γ）的能力显著低于CD8

SNX9

T细胞（

0.05）。与Anti-SNX9组相比，Anti-SNX9+Anti-PD-1组子宫颈肿瘤的生长和增殖、肿瘤组织中的SNX9、TOX蛋白表达进一步降低（

0.05），肿瘤组织中浸润性CD8

T淋巴细胞的水平和CD8

T淋巴细胞分泌功能因子TNF-α和IFN-γ的能力进一步提高（

0.05）。

结论：

SNX9/TOX信号在CC患者和小鼠模型中表现出增强的活性，并且与免疫抑制有关。针对SNX9/TOX信号通路可能是CC的潜在治疗策略。

Abstract

Background and purpose:

Immune checkpoint blockade (ICB) has become a promising strategy for treating cervical cancer (CC)

but terminal T cell depletion stil

l limits the therapeutic efficacy of ICB. The deletion of sorting nexin-9 (SNX9) can inhibit thymocyte selection-associated high mobility group box protein (TOX)

alleviate T cell exhaustion

and provide new ideas for preventing T cell exhaustion and enhancing the efficacy of cancer immunotherapy. Therefore

this study aimed to explore the immune escape mechanism mediated by the depletion of CD8

T cells induced by the SNX9/TOX signaling pathway in the CC microenvironment.

Methods:

Fifty-four peripheral blood samples were collected

including 18 from CC patients

18 from patients with high-grade squamous intraepithelial lesions (HSIL) and 18 from subjects with normal cervix. In addition

the study collected 153 pairs of CC and adjacent tissues from patients who received operation in our hospital for the first time. Clinicopathological features

tumor stages

follow-up records and other relevant clinicopathological data of CC patients were obtained from hospital records. The research was approved by the ethics committee of Changsha Fourth Hospital (approval number: 20220206). A total of 24 mice were randomly assigned to the following four groups: immunoglobulin G (IgG) group

Anti-SNX9 group

Anti-programmed death-1 (PD-1) group and Anti-SNX9

Anti-PD-1 group

with 6 mice in each group. Each group received intraperitoneal injection of blocking antibody and isotype control treatment respectively. ELISpot was used to detect the ability of CD8

T cells to secrete tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). The expressions of TOX and SNX9 in cervical cancer tissues were detected by western blot and immunohistochemistry.

Results:

The expressions of SNX9 and TOX mRNA in peripheral blood mononuclear cell (PBMC) of CC patients were higher compared with HSIL and normal controls (

0.05). The positive cell level of SNX9 and TOX immunohistochemical score were higher in CC tissue than in adjacent tissues (

=18.63

21.1

0.001). The high expression of SNX9 in CC was related to low differentiation/undifferentiation

tumor size

parauterine infiltration

vaginal infiltration

late FIGO stage and pelvic lymph node metastasis (

0.05). Compared with the low expression group of SNX9

the overall survival time of CC patients in the high expression group of SNX9 was shorter (

0.05). The percentage of CD8

SNX9

T cells was significantly higher in CC patients than in normal controls and HSIL patients (

0.05). The ability of CD8

SNX9

T cells to secrete cytokines (TNF-α and IFN-γ) was significantly lower compared with CD8

SNX9

T cells (

0.05). Compared with the Anti-SNX9 group

the growth and proliferation of cervical tumor

the expression of SNX9 and TOX protein in tumor tissue in the Anti-SNX9+Anti-PD-1 group further decreased (

0.05)

and the level of infiltrating CD8

T lymphocytes in tumor tissue and the ability of CD8

T lymphocytes to secrete functional factors TNF-α and IFN-γ further increased (

0.05).

Conclusion:

SNX9/TOX signaling pathway exhibits enhanced activity in patients with cervical cancer and mouse models

and is related to immunosuppression. Targeting SNX9/TOX signaling pathway may be a potential therapeutic strategy for CC.

关键词

Keywords

references

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