PDF(Pubmed)
Abstract：
BACKGROUND: Chemokines and cytokines are components of the tumor microenvironment and also influence tumorigenesis and its composition. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to determine the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored.
METHODS: This study leveraged summary statistics from respective genome-wide association studies (GWAS) of 109 cytokines and chemokines in 18 types of solid tumors. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The impact on immune infiltration was investigated using the TIMER and TISIDB websites. Survival analysis was conducted using the K-M plotter and TIMER 2.0 websites. The TISCH and GEO databases were used to carry out scRNA cell analysis.Analyzing relevant proteins using the STRING database and conducting enrichment pathways for GO analysis of the identified proteins.
RESULTS: The results of the inverse-variance weighted (IVW) method using cis-protein QTL (cis-pQTL) instruments showed the causal effects of TNF in reducing the risk of squamous cell lung cancer (LUSC) and HGF in reducing the risk of head and neck cancer (HNSC).The results were consistent with the eQTL. HGF was associated with better overall survival (OS) in HNSC, regardless of the types of cells enriched. However, high expression of the ligand MET for HGF leads to a decrease in overall survival in LUSC. TNF was related to poor OS in LUSC with no significant impact. However, in CD8 + T cell-enriched, eosinophil-enriched, macrophage-enriched, and NK cell-deficient types of LUSC, high expression of TNF leads to a poor prognosis, and there is statistical significance. The results showed a significant positive correlation between TNF and most immune cell infiltration, immunomodulator and chemokine in LUSC. HGF is positively correlated with the majority of immune cells except CD56 + cells, as well as some immune regulatory factors and chemotactic factors. According to single-cell sequencing results, HGF is mainly secreted by fibroblasts and myofibroblasts in HNSC, while in LUSC, it is primarily secreted by macrophages and CD8 + T cells secrete TNF. The GO/KEGG analysis suggests that proteins related to HGF are mainly involved in regulating peptidyl-tyrosine phosphorylation and positive regulation of the MAPK cascade. Proteins related to TNF are primarily associated with the regulation of I-kappaB kinase/NF-kappaB signaling and cytokine-mediated signaling pathway.
CONCLUSIONS: HGF is primarily secreted by fibroblasts in HNSC and may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not necessarily be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it\'s impact on the prognosis of LUSC through the immune microenvironment may have a different effect.
Chemokines and cytokines are not only components of the tumor microenvironment but also affect tumorigenesis and the composition of the tumor microenvironment. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to define the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored. This study leveraged the summary statistic from respective genome wide association study (GWAS) of 109 cytokines and chemokines to 18 types of solid tumor. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The results showed HGF is primarily secreted by fibroblasts in HNSC, and it may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it’s impact on the prognosis of LUSC through the immune microenvironment may have a different effect.
METHODS: This study leveraged summary statistics from respective genome-wide association studies (GWAS) of 109 cytokines and chemokines in 18 types of solid tumors. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The impact on immune infiltration was investigated using the TIMER and TISIDB websites. Survival analysis was conducted using the K-M plotter and TIMER 2.0 websites. The TISCH and GEO databases were used to carry out scRNA cell analysis.Analyzing relevant proteins using the STRING database and conducting enrichment pathways for GO analysis of the identified proteins.
RESULTS: The results of the inverse-variance weighted (IVW) method using cis-protein QTL (cis-pQTL) instruments showed the causal effects of TNF in reducing the risk of squamous cell lung cancer (LUSC) and HGF in reducing the risk of head and neck cancer (HNSC).The results were consistent with the eQTL. HGF was associated with better overall survival (OS) in HNSC, regardless of the types of cells enriched. However, high expression of the ligand MET for HGF leads to a decrease in overall survival in LUSC. TNF was related to poor OS in LUSC with no significant impact. However, in CD8 + T cell-enriched, eosinophil-enriched, macrophage-enriched, and NK cell-deficient types of LUSC, high expression of TNF leads to a poor prognosis, and there is statistical significance. The results showed a significant positive correlation between TNF and most immune cell infiltration, immunomodulator and chemokine in LUSC. HGF is positively correlated with the majority of immune cells except CD56 + cells, as well as some immune regulatory factors and chemotactic factors. According to single-cell sequencing results, HGF is mainly secreted by fibroblasts and myofibroblasts in HNSC, while in LUSC, it is primarily secreted by macrophages and CD8 + T cells secrete TNF. The GO/KEGG analysis suggests that proteins related to HGF are mainly involved in regulating peptidyl-tyrosine phosphorylation and positive regulation of the MAPK cascade. Proteins related to TNF are primarily associated with the regulation of I-kappaB kinase/NF-kappaB signaling and cytokine-mediated signaling pathway.
CONCLUSIONS: HGF is primarily secreted by fibroblasts in HNSC and may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not necessarily be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it\'s impact on the prognosis of LUSC through the immune microenvironment may have a different effect.
Chemokines and cytokines are not only components of the tumor microenvironment but also affect tumorigenesis and the composition of the tumor microenvironment. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to define the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored. This study leveraged the summary statistic from respective genome wide association study (GWAS) of 109 cytokines and chemokines to 18 types of solid tumor. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The results showed HGF is primarily secreted by fibroblasts in HNSC, and it may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it’s impact on the prognosis of LUSC through the immune microenvironment may have a different effect.
摘要：
背景：趋化因子和细胞因子是肿瘤微环境的组成部分，也影响肿瘤发生及其组成。然而,他们是否遗传代理肿瘤发生尚不清楚。对于因果关系，eQTL和pQTL用于确定趋化因子和细胞因子在泛癌症中的作用。还探讨了对肿瘤免疫微环境的影响。
方法：本研究利用了18种实体瘤中109种细胞因子和趋化因子各自的全基因组关联研究（GWAS）的汇总统计。单核苷酸多态性（SNP）与细胞因子和趋化因子密切相关，位于或接近其编码基因（顺式），被用作工具变量。采用了两个样本的MR设计，然后进行全面的敏感性分析，以验证结果的稳健性。使用TIMER和TISIDB网站研究了对免疫浸润的影响。使用K-M绘图仪和TIMER2.0网站进行生存分析。使用TISCH和GEO数据库进行scRNA细胞分析。使用STRING数据库分析相关蛋白质，并进行富集途径以对鉴定的蛋白质进行GO分析。
结果：使用顺式蛋白QTL（cis-pQTL）仪器的逆方差加权（IVW）方法的结果显示，TNF在降低鳞状细胞肺癌（LUSC）和HGF在降低头颈癌（HNSC）风险方面具有因果关系。结果与eQTL一致。HGF与HNSC更好的总生存期（OS）相关，无论富集的细胞类型。然而,HGF配体MET的高表达导致LUSC的总体存活率降低.TNF与LUSC不良OS相关，无明显影响。然而,在CD8+T细胞富集，嗜酸性粒细胞富集，富含巨噬细胞，和缺乏NK细胞的LUSC类型，TNF的高表达导致不良预后,有统计学意义。结果显示TNF与大多数免疫细胞浸润呈显著正相关,LUSC中的免疫调节剂和趋化因子。HGF与除CD56+细胞外的大多数免疫细胞呈正相关,以及一些免疫调节因子和趋化因子。根据单细胞测序结果,HGF主要由HNSC中的成纤维细胞和肌成纤维细胞分泌,而在LUSC,主要由巨噬细胞分泌,CD8+T细胞分泌TNF。GO/KEGG分析表明，与HGF相关的蛋白质主要参与调节肽基酪氨酸磷酸化和MAPK级联的正调节。与TNF相关的蛋白主要与I-κB激酶/NF-κB信号传导和细胞因子介导的信号传导途径的调节有关。
结论：HGF主要由HNSC中的成纤维细胞分泌，可能对HNSC的发生和预后具有保护作用。这些影响独立于免疫细胞的影响，这种作用可能不一定是通过HGF/MET途径介导的。另一方面,LUSC中的TNF主要由免疫细胞如CD8+T细胞分泌,可能对LUSC的发生有保护作用。然而,它通过免疫微环境对LUSC预后的影响可能有不同的作用。
趋化因子和细胞因子不仅是肿瘤微环境的组成部分，而且还影响肿瘤发生和肿瘤微环境的组成。然而,他们是否遗传代理肿瘤发生尚不清楚。对于因果关系，eQTL和pQTL用于定义趋化因子和细胞因子在泛癌症中的作用。还探讨了对肿瘤免疫微环境的影响。这项研究利用了来自109种细胞因子和趋化因子的相应全基因组关联研究（GWAS）的汇总统计量对18种实体瘤。单核苷酸多态性（SNP）与细胞因子和趋化因子密切相关，位于或接近其编码基因（顺式），被用作工具变量。采用了两个样本的MR设计，然后进行全面的敏感性分析，以验证结果的稳健性。结果显示HGF主要由HNSC中的成纤维细胞分泌,可能对HNSC的发生和预后有一定的保护作用。这些影响独立于免疫细胞的影响，这种作用可能不是通过HGF/MET途径介导的。另一方面,LUSC中的TNF主要由免疫细胞如CD8+T细胞分泌,可能对LUSC的发生有保护作用。然而,它通过免疫微环境对LUSC预后的影响可能有不同的影响。
方法：本研究利用了18种实体瘤中109种细胞因子和趋化因子各自的全基因组关联研究（GWAS）的汇总统计。单核苷酸多态性（SNP）与细胞因子和趋化因子密切相关，位于或接近其编码基因（顺式），被用作工具变量。采用了两个样本的MR设计，然后进行全面的敏感性分析，以验证结果的稳健性。使用TIMER和TISIDB网站研究了对免疫浸润的影响。使用K-M绘图仪和TIMER2.0网站进行生存分析。使用TISCH和GEO数据库进行scRNA细胞分析。使用STRING数据库分析相关蛋白质，并进行富集途径以对鉴定的蛋白质进行GO分析。
结果：使用顺式蛋白QTL（cis-pQTL）仪器的逆方差加权（IVW）方法的结果显示，TNF在降低鳞状细胞肺癌（LUSC）和HGF在降低头颈癌（HNSC）风险方面具有因果关系。结果与eQTL一致。HGF与HNSC更好的总生存期（OS）相关，无论富集的细胞类型。然而,HGF配体MET的高表达导致LUSC的总体存活率降低.TNF与LUSC不良OS相关，无明显影响。然而,在CD8+T细胞富集，嗜酸性粒细胞富集，富含巨噬细胞，和缺乏NK细胞的LUSC类型，TNF的高表达导致不良预后,有统计学意义。结果显示TNF与大多数免疫细胞浸润呈显著正相关,LUSC中的免疫调节剂和趋化因子。HGF与除CD56+细胞外的大多数免疫细胞呈正相关,以及一些免疫调节因子和趋化因子。根据单细胞测序结果,HGF主要由HNSC中的成纤维细胞和肌成纤维细胞分泌,而在LUSC,主要由巨噬细胞分泌,CD8+T细胞分泌TNF。GO/KEGG分析表明，与HGF相关的蛋白质主要参与调节肽基酪氨酸磷酸化和MAPK级联的正调节。与TNF相关的蛋白主要与I-κB激酶/NF-κB信号传导和细胞因子介导的信号传导途径的调节有关。
结论：HGF主要由HNSC中的成纤维细胞分泌，可能对HNSC的发生和预后具有保护作用。这些影响独立于免疫细胞的影响，这种作用可能不一定是通过HGF/MET途径介导的。另一方面,LUSC中的TNF主要由免疫细胞如CD8+T细胞分泌,可能对LUSC的发生有保护作用。然而,它通过免疫微环境对LUSC预后的影响可能有不同的作用。
趋化因子和细胞因子不仅是肿瘤微环境的组成部分，而且还影响肿瘤发生和肿瘤微环境的组成。然而,他们是否遗传代理肿瘤发生尚不清楚。对于因果关系，eQTL和pQTL用于定义趋化因子和细胞因子在泛癌症中的作用。还探讨了对肿瘤免疫微环境的影响。这项研究利用了来自109种细胞因子和趋化因子的相应全基因组关联研究（GWAS）的汇总统计量对18种实体瘤。单核苷酸多态性（SNP）与细胞因子和趋化因子密切相关，位于或接近其编码基因（顺式），被用作工具变量。采用了两个样本的MR设计，然后进行全面的敏感性分析，以验证结果的稳健性。结果显示HGF主要由HNSC中的成纤维细胞分泌,可能对HNSC的发生和预后有一定的保护作用。这些影响独立于免疫细胞的影响，这种作用可能不是通过HGF/MET途径介导的。另一方面,LUSC中的TNF主要由免疫细胞如CD8+T细胞分泌,可能对LUSC的发生有保护作用。然而,它通过免疫微环境对LUSC预后的影响可能有不同的影响。
