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G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2020-07-13 , DOI: 10.3389/fimmu.2020.01885
Ioannis Karagiannidis 1 , Stephanie J Jerman 2 , Damian Jacenik 3, 4 , Brandon B Phinney 2 , Ruoxin Yao 1 , Eric R Prossnitz 3 , Ellen J Beswick 1
Affiliation  

Cytokines are known to shape the tumor microenvironment and although progress has been made in understanding their role in carcinogenesis, much remains to learn regarding their role in tumor growth and progression. We have identified granulocyte colony-stimulating factor (G-CSF) as one such cytokine, showing that G-CSF is linked with metastasis in human gastrointestinal tumors and neutralizing G-CSF in a mouse model of colitis-associated cancer is protective. Here, we set out to identify the role of G-CSF and its receptor, G-CSFR, in CD4+ and CD8+ T cell responses in the tumor microenvironment. MC38 colon cancer cells were injected into WT, G-CSFR−/− mice, or Rag2−/− mice. Flow cytometry, Real Time PCR and Multiplex cytokine array analysis were used for in vitro T cell phenotype analysis. Adoptive transfer of WT or G-CSFR−/− CD4+ of CD8+ T cells were performed. Mouse tumor size, cytokine expression, T cell phenotype, and cytotoxic activity were analyzed. We established that in G-CSFR−/− mice, tumor growth of MC38 colon cancer cells is significantly decreased. T cell phenotype and cytokine production were also altered, as both in vitro and in vivo approaches revealed that the G-CSF/G-CSFR stimulate IL-10-producing, FoxP3-expressing CD4+ and CD8+ T cells, whereas G-CSFR−/− T cells exhibit increased IFNγ and IL-17A production, leading to increased cytotoxic activity in the tumor microenvironment. Furthermore, peritumoral injection of recombinant IFNγ or IL-17A inhibited colon and pancreas tumor growth compared to controls. Taken together, our data reveal an unknown mechanism by which G-CSF, through its receptor G-CSFR, promotes an inhibitory Treg phenotype that limits tumor immune responses and furthermore suggest that targeting this cytokine/receptor axis could represent a novel therapeutic approach for gastrointestinal, and likely other tumors with high expression of these factors.



中文翻译:

G-CSF 和 G-CSFR 调节 CD4 和 CD8 T 细胞反应以促进结肠肿瘤生长并且是潜在的治疗靶点

众所周知,细胞因子可以塑造肿瘤微环境,尽管在了解它们在致癌作用中的作用方面已经取得了进展,但关于它们在肿瘤生长和进展中的作用还有很多需要了解的地方。我们已将粒细胞集落刺激因子 (G-CSF) 鉴定为此类细胞因子之一,表明 G-CSF 与人胃肠道肿瘤的转移有关,并且在结肠炎相关癌症小鼠模型中中和 G-CSF 具有保护作用。在这里,我们着手确定 G-CSF 及其受体 G-CSFR 在肿瘤微环境中CD4 +和 CD8 + T 细胞反应中的作用。将 MC38 结肠癌细胞注射到 WT、G-CSFR -/-小鼠或 Rag2 -/-中老鼠。流式细胞术、实时 PCR 和多重细胞因子阵列分析用于体外T 细胞表型分析。进行了WT 或 G-CSFR -/- CD4 +的 CD8 + T 细胞的过继转移。分析了小鼠肿瘤大小、细胞因子表达、T 细胞表型和细胞毒活性。我们确定在 G-CSFR -/-小鼠中,MC38 结肠癌细胞的肿瘤生长显着降低。T 细胞表型和细胞因子的产生也发生了改变,因为两者体外体内方法表明,G-CSF/G-CSFR 刺激产生 IL-10、表达 FoxP3 的 CD4 +和 CD8 + T 细胞,而 G-CSFR -/- T 细胞表现出增加的 IFNγ 和 IL-17A 产生,导致增加肿瘤微环境中的细胞毒活性。此外,与对照组相比,瘤周注射重组 IFNγ 或 IL-17A 可抑制结肠和胰腺肿瘤的生长。综上所述,我们的数据揭示了一种未知的机制,G-CSF 通过其受体 G-CSFR 促进抑制性 Treg 表型,从而限制肿瘤免疫反应,并进一步表明靶向该细胞因子/受体轴可能代表一种新的胃肠道治疗方法,以及可能具有这些因子高表达的其他肿瘤。

更新日期:2020-09-15
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