基于癌症免疫周期筛选结直肠癌免疫联合治疗的新靶点

曾薇; 唐菊彬; 陈向宙; 陈玮; 杨丹; 朱金峰

doi:10.16766/j.cnki.issn.1674-4152.003829

基于癌症免疫周期筛选结直肠癌免疫联合治疗的新靶点

doi: 10.16766/j.cnki.issn.1674-4152.003829

曾薇¹,
唐菊彬¹,
陈向宙¹,
陈玮¹,
杨丹¹,
朱金峰^2, ,

1.
华南理工大学附属第六医院肿瘤医学中心四区，广东佛山 528200
2.
华南理工大学附属第六医院胃肠外科

基金项目:

国家自然科学基金青年科学基金项目 82103636

广东省基础与应用基础研究基金自然科学基金项目 2022A1515012613

详细信息

通讯作者:
朱金峰，E-mail：1533640679@qq.com

中图分类号: R735.35 R735.37
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- 文章访问数: 37
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- PDF下载量: 1
- 被引次数: 0
出版历程
- 收稿日期: 2024-04-30
- 网络出版日期: 2025-02-13

Screening novel targets for combination immunotherapy of colorectal cancer based on cancer immune cycle

1.
The Forth Department of Cancer Center, the Sixth Affiliated Hospital of South China University of Technology, Foshan, Guangdong 528200, China

摘要

摘要: 目的目前免疫检查点抑制剂(ICI)已批准用于治疗不可切除或转移性高度微卫星不稳定型/错配修复缺陷型(dMMR/MSI-H型)结直肠癌患者。然而，约50%的dMMR/MSI-H型患者对ICI原发性耐药，而MSS/pMMR型患者对单药ICI的反应有限，因此目前亟待寻找免疫联合治疗的新靶点，进一步改善患者ICI的治疗疗效。方法本研究将癌症免疫周期评分与加权基因共表达网络和系统分析相结合，以筛选结直肠癌中的免疫抑制基因；使用GEPIA2数据库分析基因在结直肠癌组织中的表达特征；CIBERSORT评估基因表达与免疫细胞浸润水平的相关性；TIDE算法预测基因表达与患者免疫治疗疗效的关系；Kaplan-Meier生存分析比较基因高、低表达水平组接受免疫治疗后的预后差异；GSEA分析基因参与结直肠癌的发生、发展，影响患者预后的调控机制。结果癌症免疫周期评分、加权基因共表达网络和系统分析提示DDX27是结直肠癌免疫联合治疗的新靶点；DDX27在结直肠癌组织中呈显著高表达(P < 0.001)，与患者较晚的N分期(P=0.005)、TNM分期(P=0.006)和抑制性免疫细胞的浸润水平呈正相关关系；DDX27高水平表达组患者接受免疫治疗的疗效不佳，且该组患者接受ICI治疗后的总生存期短于DDX27低水平表达组(7.2个月vs. 9.6个月)；进一步分析显示DDX27可能通过调控RNA加工、代谢参与结直肠癌的发生、发展，影响患者的预后。结论鉴于DDX27可能通过促进抑制性免疫细胞浸润，调控RNA加工和代谢参与结直肠癌的发生、发展，因此靶向干扰DDX27可能作为结直肠癌免疫联合治疗的新策略。
- 结直肠癌 /
- 癌症免疫周期 /
- 免疫治疗
Abstract: Objective At this stage, immune checkpoint inhibitors (ICIs) are approved for the treatment of colorectal cancer. However, about 50% of dMMR/MSI-H-type patients are primarily resistant to ICIs, and MSS/pMMR-type patients have limited response to single-agent ICIs; therefore, there is an urgent need to find new targets for immune-combination therapy to further improve the therapeutic efficacy of ICIs in patients. Methods In this study, we combined the Cancer Immune Cycle Score with the weighted gene co-expression network and systematic analyses to screen immunosuppressive genes in colorectal cancer; analyzed gene expression profiles in colorectal cancer tissues using the GEPIA2 database; CIBERSORT assessed the correlation between gene expression and the level of immune cell infiltration; the TIDE algorithm predicted the gene expression in relation to the efficacy of patient immunotherapy relationship; Kaplan-Meier survival analysis to compare the prognostic differences between groups with high and low expression levels of genes after receiving immunotherapy; and GSEA to analyze the regulatory mechanisms of genes involved in colorectal cancer genesis, development, and affecting the prognosis of patients. Results Cancer immune cycle score with weighted gene co-expression network and systematic analysis showed that DDX27 was an immunosuppressive target of colorectal cancer; DDX27 was significantly highly expressed in colorectal cancer tissues (P < 0.001), which was positively correlated with the patients ' later N stage (P=0.005), TNM stage (P=0.006) and infiltration level of suppressive immune cells; patients in the group with high levels of DDX27 expression were poorly treated with immunotherapy, and the overall survival of patients in this group treated with ICI was shorter than that in the group with low levels of DDX27 expression (7.2 months vs. 9.6 months); further analysis showed that DDX27 might be involved in the occurrence and development of colorectal cancer through the regulation of RNA processing and metabolism, and affect the prognosis of patients. Conclusion Targeting DDX27 may be a new target for immunotherapy of colorectal cancer by inhibiting the infiltration of immunosuppressive cells and interfering with tumorigenesis and development.
- Colorectal cancer /
- Cancer immune cycle /
- Immunotherapy

HTML全文

图 1 基于CIC信息对结直肠癌数据进行WGCNA分析

注：基因集合模块与CIC的相关性热图，其中tan模块与CIC呈最显著负相关，darkorange与CIC呈最显著正相关。

Figure 1. WGCNA analysis of colorectal cancer data based on CIC information

下载: 全尺寸图片幻灯片

图 2 基因在结直肠癌组织中的差异表达及与darkorange模块的相关性

注：GEPIA2数据库中6个基因在结直肠癌组织中的差异表达。^aP＜0.05。

Figure 2. Differential gene expression in colorectal cancer tissues and its correlation with the darkorange module

下载: 全尺寸图片幻灯片

图 3 DDX27的表达水平与结直肠癌患者接受免疫治疗后总生存的相关性

Figure 3. Correlation between DDX27 expression levels and overall survival after immunotherapy in patients with colorectal cancer

下载: 全尺寸图片幻灯片

表 1 不同DDX27表达水平结直肠癌患者临床病理特征比较[例(%)]

Table 1. Correlation analysis between DDX27 expression levels and clinicopathological features in colorectal cancer patients[cases(%)]

项目	DDX27低水平表达(n=322)	DDX27高水平表达(n=322)	χ²值	P值
T分期			0.221	0.639
T1 & T2	65(10.1)	69(10.7)
T3 & T4	257(39.9)	253(39.3)
N分期			7.766	0.005
N0	202(31.4)	168(26.1)
N1~N2	120(18.6)	154(23.9)
M分期			3.529	0.060
M0	271(42.1)	256(39.8)
M1	51(7.9)	66(10.3)
TNM分期			7.620	0.006
Ⅰ~Ⅱ期	201(31.2)	158(24.5)
Ⅲ~Ⅳ期	121(18.8)	164(25.5)
性别			0.056	0.813
女性	152(23.6)	149(23.1)
男性	170(26.4)	173(26.9)
年龄			14.609	0.001
≤65岁	114(17.7)	162(25.2)
>65岁	208(32.3)	160(24.8)

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