Mechanism of immune escape mediated by T cell depletion induced by TOX signaling pathway in cervical cancer microenvironment

Dan LIU; Guxiang ZHANG; Dan XIE; Yan XU; Chengfang XIE; Yuxi TANG

doi:10.19401/j.cnki.1007-3639.2025.07.007

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Mechanism of immune escape mediated by T cell depletion induced by TOX signaling pathway in cervical cancer microenvironment

Article | 更新时间：2025-12-31

- Mechanism of immune escape mediated by T cell depletion induced by TOX signaling pathway in cervical cancer microenvironment
- China Oncology Vol. 35, Issue 7, Pages: 685-694(2025)
- 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：
- 基金信息：
  
  Hunan Provincial Health Commission Scientific Research Project(D20230217951)
- DOI：10.19401/j.cnki.1007-3639.2025.07.007
  CLC： R737.33
- Received：23 October 2024，
  
  Revised：2025-02-06，
  
  Published：30 July 2025
- 稿件说明：
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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：

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

HUANG J J , DENG Y Y , BOAKYE D , et al . Global distribution, risk factors, and recent trends for cervical cancer: a worldwide country-level analysis [J ] . Gynecol Oncol , 2022 , 164 ( 1 ): 85 - 92 .

SINGH D , VIGNAT J , LORENZONI V , et al . Global estimates of incidence and mortality of cervical cancer in 2020: a baseline analysis of the WHO Global Cervical Cancer Elimination Initiative [J ] . Lancet Glob Health , 2023 , 11 ( 2 ): e197-e206.

LIU L , WANG A H , LIU X L , et al . Blocking TIGIT/CD155 signalling reverses CD8 + T cell exhaustion and enhances the antitumor activity in cervical cancer [J ] . J Transl Med , 2022 , 20 ( 1 ): 280 .

SHARMA P , GOSWAMI S , RAYCHAUDHURI D , et al . Immune checkpoint therapy-current perspectives and future directions [J ] . Cell , 2023 , 186 ( 8 ): 1652 - 1669 . DOI: 10.1016/j.cell.2023.03.006 http://doi.org/10.1016/j.cell.2023.03.006

LORUSSO D , XIANG Y , HASEGAWA K , et al . Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial [J ] . Lancet , 2024 , 403 ( 10434 ): 1341 - 1350 . DOI: 10.1016/S0140-6736(24)00317-9 http://doi.org/10.1016/S0140-6736(24)00317-9

OAKNIN A , MOORE K , MEYER T , et al . Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial [J ] . Lancet Oncol , 2024 , 25 ( 5 ): 588 - 602 . DOI: 10.1016/S1470-2045(24)00088-3 http://doi.org/10.1016/S1470-2045(24)00088-3

TREFNY M P , KIRCHHAMMER N , DER MAUR P A , et al . Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy [J ] . Nat Commun , 2023 , 14 ( 1 ): 86 . DOI: 10.1038/s41467-022-35583-w http://doi.org/10.1038/s41467-022-35583-w

PHILIP M , SCHIETINGER A . CD8 + T cell differentiation and dysfunction in cancer [J ] . Nat Rev Immunol , 2022 , 22 ( 4 ): 209 - 223 .

CHEN J , SONG Y , MIAO F , et al . PDL1-positive exosomes suppress antitumor immunity by inducing tumor-specific CD8 + T cell exhaustion during metastasis [J ] . Cancer Sci , 2021 , 112 ( 9 ): 3437 - 3454 .

BAI R L , LV Z , XU D S , et al . Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors [J ] . Biomark Res , 2020 , 8 : 34 . DOI: 10.1186/s40364-020-00209-0 http://doi.org/10.1186/s40364-020-00209-0

MAKUKU R , KHALILI N , RAZI S , et al . Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy [J ] . J Immunol Res , 2021 , 2021 : 6661406 .

WANG Y Z , WANG J S , DU J , et al . Clinical benefit analysis of PD-1 inhibitors in patients with advanced, recurrent or metastatic cervical cancer: a meta-analysis and systematic review [J ] . Front Immunol , 2024 , 15 : 1305810 .

LEE J B , KHAN D H , HURREN R , et al . Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production [J ] . Blood , 2021 , 138 ( 3 ): 234 - 245 .

WEI W , CHEN Z N , WANG K . CRISPR/Cas9: a powerful strategy to improve CAR-T cell persistence [J ] . Int J Mol Sci , 2023 , 24 ( 15 ): 12317 .

NIU H Y , WANG H Q . TOX regulates T lymphocytes differentiation and its function in tumor [J ] . Front Immunol , 2023 , 14 : 990419 .

AHMAD A , ANSARI I A . Carvacrol exhibits chemopreventive potential against cervical cancer cells via caspase-dependent apoptosis and abrogation of cell cycle progression [J ] . Anticancer Agents Med Chem , 2021 , 21 ( 16 ): 2224 - 2235 .

FENG X , SHAN R , HU X M . The linkage of NF-κB signaling pathway-associated long non-coding RNAs with tumor microenvironment and prognosis in cervical cancer [J ] . BMC Med Genomics , 2023 , 16 ( 1 ): 169 . DOI: 10.1186/s12920-023-01605-9 http://doi.org/10.1186/s12920-023-01605-9

WANG D J , ZOU F , LI Y , et al . Targeting MELK improves PD-1 blockade efficiency in cervical cancer via enhancing antitumor immunity [J ] . Mol Ther Oncol , 2024 , 32 ( 1 ): 200759 .

BORST J , BUSSELAAR J , BOSMA D M T , et al . Mechanism of action of PD-1 receptor/ligand targeted cancer immunotherapy [J ] . Eur J Immunol , 2021 , 51 ( 8 ): 1911 - 1920 . DOI: 10.1002/eji.202048994 http://doi.org/10.1002/eji.202048994

BUDIMIR N , THOMAS G D , DOLINA J S , et al . Reversing T-cell exhaustion in cancer: lessons learned from PD-1/PD-L1 immune checkpoint blockade [J ] . Cancer Immunol Res , 2022 , 10 ( 2 ): 146 - 153 .

CILLO A R , CARDELLO C , SHAN F , et al . Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8 + T cells to promote antitumor immunity [J ] . Cell , 2024 , 187 ( 16 ): 4373 - 4388 .e15.

ECKER M , SCHREGLE R , KAPOOR-KAUSHIK N , et al . SNX9 - induced membrane tubulation regulates CD28 cluster stability and signalling [J ] . eLife , 2022 , 11: e67550.

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