目的研究内蒙古地区蒙古族人群白细胞介素15受体α亚单位(interleukin-15 receptorαsubunits,IL-15Rα)及Runt相关转录因子2(recombinant Runt related transcription factor 2,RUNX2)基因多态性与后纵韧带骨化(ossification of poster...目的研究内蒙古地区蒙古族人群白细胞介素15受体α亚单位(interleukin-15 receptorαsubunits,IL-15Rα)及Runt相关转录因子2(recombinant Runt related transcription factor 2,RUNX2)基因多态性与后纵韧带骨化(ossification of posterior longitudinal ligament,OPLL)的关系。方法采用基因测序法选择2014年1月至2019年12月就诊于我院的蒙古族OPLL患者以及同期健康体检的蒙族人群为研究对象,110例内蒙古地区蒙古族后纵韧带骨化患者和118例健康蒙古族人群进行IL-15Rα基因及RUNX2基因多态性的检测。110例内蒙古地区蒙古族后纵韧带骨化患者,其中男75例,女35例;年龄38~78岁,平均(53.0±12.8)岁。118例健康蒙古族人群,其中男65例,女53例;年龄45~68岁,平均(58.0±11.2)岁。两组IL-15Rα基因及RUNX2基因进行比较,筛选出有意义基因。结果两组采用χ^(2)检验对rs1321075位点基因型、等位基因频率进行比较,AC、CC型差异有统计学意义(P<0.05),OR值(95%CI)分别为0.584(0.343,0.997)、1.978(1.166,3.353),等位基因C的OR值(95%CI)为0.588(0.386,0.895);对rs16873379位点基因型、等位基因频率进行比较,CT、TT型差异有统计学意义(P<0.05),OR值(95%CI)分别为2.756(1.595,4.760)、0.266(0.153,0.461),等位基因C的OR值(95%CI)为2.514(1.678,3.768);对rs2296139位点基因型、等位基因频率进行比较,AA基因型差异有统计学意义(P<0.05),OR值(95%CI)为0.416(0.218,0.797);其他位点基因型、等位基因频率进行比较,差异无统计学意义(P>0.05)。结论RUNX2基因及IL-15Rα基因中rs1321075位点和rs2296139位点多态性在内蒙古地区蒙古族后纵韧带骨化人群中可能发挥作用。展开更多
Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and im...Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.展开更多
文摘目的研究内蒙古地区蒙古族人群白细胞介素15受体α亚单位(interleukin-15 receptorαsubunits,IL-15Rα)及Runt相关转录因子2(recombinant Runt related transcription factor 2,RUNX2)基因多态性与后纵韧带骨化(ossification of posterior longitudinal ligament,OPLL)的关系。方法采用基因测序法选择2014年1月至2019年12月就诊于我院的蒙古族OPLL患者以及同期健康体检的蒙族人群为研究对象,110例内蒙古地区蒙古族后纵韧带骨化患者和118例健康蒙古族人群进行IL-15Rα基因及RUNX2基因多态性的检测。110例内蒙古地区蒙古族后纵韧带骨化患者,其中男75例,女35例;年龄38~78岁,平均(53.0±12.8)岁。118例健康蒙古族人群,其中男65例,女53例;年龄45~68岁,平均(58.0±11.2)岁。两组IL-15Rα基因及RUNX2基因进行比较,筛选出有意义基因。结果两组采用χ^(2)检验对rs1321075位点基因型、等位基因频率进行比较,AC、CC型差异有统计学意义(P<0.05),OR值(95%CI)分别为0.584(0.343,0.997)、1.978(1.166,3.353),等位基因C的OR值(95%CI)为0.588(0.386,0.895);对rs16873379位点基因型、等位基因频率进行比较,CT、TT型差异有统计学意义(P<0.05),OR值(95%CI)分别为2.756(1.595,4.760)、0.266(0.153,0.461),等位基因C的OR值(95%CI)为2.514(1.678,3.768);对rs2296139位点基因型、等位基因频率进行比较,AA基因型差异有统计学意义(P<0.05),OR值(95%CI)为0.416(0.218,0.797);其他位点基因型、等位基因频率进行比较,差异无统计学意义(P>0.05)。结论RUNX2基因及IL-15Rα基因中rs1321075位点和rs2296139位点多态性在内蒙古地区蒙古族后纵韧带骨化人群中可能发挥作用。
基金National Key Research and Development Plan,Grant/Award Number:2017YFA0506000Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2021B1515120016+1 种基金National Natural Science Foundation of China,Grant/Award Number:82072822the Key Research and Development Program of Jiangsu Province,China-Social Development Projects,Grant/Award Number:BE2020687。
文摘Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.
