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Published on: July 20, 2014
CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1-CXCR2 induced NETs
Gan Xiong1, Zhi Chen1, Qianwen Liu2
1Center for Translational Medicine, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China.
Background:
CD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping immune surveillance in a variety of tumors; however, the underlying mechanisms facilitating immune escape in esophageal squamous cell carcinoma (ESCC) remain enigmatic.
Methods:
We investigated the expression of CD276 in ESCC tissues from patients by using immunohistochemistry (IHC) assays. In vivo, we established a 4-nitroquinoline 1-oxide (4NQO)-induced CD276 knockout (CD276wKO) and K14cre; CD276 conditional knockout (CD276cKO) mouse model of ESCC to study the functional role of CD276 in ESCC. Furthermore, we used the 4NQO-induced mouse model to evaluate the effects of anti-CXCL1 antibodies, anti-Ly6G antibodies, anti-NK1.1 antibodies, and GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, and immunofluorescence techniques were employed to measure immune cell proportions in ESCC. In addition, we conducted single-cell RNA sequencing analysis to examine the alterations in tumor microenvironment following CD276 depletion.
Results:
In this study, we elucidate that CD276 is markedly upregulated in ESCC, correlating with poor prognosis. In vivo, our results indicate that depletion of CD276 inhibits tumorigenesis and progression of ESCC. Furthermore, conditional knockout of CD276 in epithelial cells engenders a significant downregulation of CXCL1, consequently reducing the formation of neutrophil extracellular trap networks (NETs) via the CXCL1-CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. In addition, overexpression of CD276 promotes tumorigenesis via increasing NETs' formation and reducing NK cells in vivo.
Conclusions:
This study successfully elucidates the functional role of CD276 in ESCC. Our comprehensive analysis uncovers the significant role of CD276 in modulating immune surveillance mechanisms in ESCC, thereby suggesting that targeting CD276 might serve as a potential therapeutic approach for ESCC treatment.
Insights
CD276 (B7-H3) is upregulated in esophageal squamous cell carcinoma (ESCC), promoting tumor growth by increasing neutrophil extracellular traps (NETs) and decreasing natural killer (NK) cells. Targeting CD276 may offer a new therapeutic strategy for ESCC.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- CD276 (B7-H3) is an immune checkpoint protein implicated in tumor progression across various cancers.
- Its role in immune evasion within esophageal squamous cell carcinoma (ESCC) remains poorly understood.
- Understanding CD276's function is crucial for developing effective ESCC therapies.
Purpose of the Study:
- To investigate the expression and functional role of CD276 in esophageal squamous cell carcinoma (ESCC).
- To elucidate the mechanisms by which CD276 influences the tumor immune microenvironment in ESCC.
- To evaluate CD276 as a potential therapeutic target for ESCC.
Main Methods:
- Immunohistochemistry (IHC) to assess CD276 expression in ESCC patient tissues.
- Development of CD276 knockout mouse models (4NQO-induced and K14cre; CD276 conditional knockout) for in vivo studies.
- Flow cytometry, immunofluorescence, and single-cell RNA sequencing to analyze immune cell populations and tumor microenvironment alterations.
Main Results:
- CD276 is significantly upregulated in ESCC and correlates with poor patient prognosis.
- CD276 depletion inhibits ESCC tumorigenesis and progression in vivo.
- Loss of CD276 downregulates CXCL1, reduces neutrophil extracellular trap (NET) formation via the CXCL1-CXCR2 axis, and enhances natural killer (NK) cell activity.
Conclusions:
- CD276 plays a critical role in modulating immune surveillance in esophageal squamous cell carcinoma (ESCC).
- The study reveals CD276's mechanism involving CXCL1, NETs, and NK cells in ESCC progression.
- Targeting CD276 presents a promising therapeutic avenue for treating esophageal squamous cell carcinoma.
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