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Super-enhancer receives signals from the extracellular matrix to induce PD-L1-mediated immune evasion via integrin/ BRAF/TAK1/ERK/ETv4 signaling

引用

Cancer Biology & Medicine 2022年第5期19卷 669-684页

作者： Panpan Ma Xinxin Jin Zhiwei Fan Zhou Wang Suhui Yue Changyue Wu Shiyin Chen Yuanyuan Wu Miaomiao Chen Donghua Gu Siliang Zhang Renfang Mao Yihui Fan Laboratory of Medical Science School of MedicineNantong UniversityNantong 226001China Department of Pathogenic Biology School of MedicineNantong UniversityNantong 226001China Department of Clinical Laboratory Yancheng No.1 People’s HospitalYancheng 224005China School of Life Sciences Nantong UniversityNantong 226001China Department of Dermatology Affiliated Hospital of Nantong UniversityNantong UniversityNantong 226001China The Department of Urology the Second Affiliated Hospital of Nantong UniversityNantong UniversityNantong 226001China The Department of Radiotherapy Oncology Harbin Medical University Cancer HospitalHarbin 150086China Department of Pathophysiology School of MedicineNantong UniversityNantong 226001China

Objective:PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade.The factors that drive inducible PD-L1 expression have been extensively studied,but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown.Methods:DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout.Protein function was inhibited by chemical inhibitors.Protein levels were examined by Western blot,mRNA levels were examined by real-time RT-PCR,and surface protein expression was determined by cellular immunofluorescence and flow cytometry.Immune evasion was examined by in vitro T cell-mediated killing.Results:We determined the core regions(chr9:5,496,378–5,499,663)of a previously identified PD-L1L2-super-enhancer(SE).Through systematic analysis,we found that the E26 transformation-specific(ETS)variant transcription factor(ETv4)bound to this core DNA region but not to DNA surrounding PD-L1L2SE.Genetic knockout of ETv4 dramatically reduced the expressions of both PD-L1 and PD-L2.ETv4 transcription was dependent on ERK activation,and BRAF/TAK1-induced ERK activation was dependent on extracellular signaling fromαvβ3 integrin,which profoundly affected ETv4 transcription and PD-L1/L2 expression.Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing.Conclusions:We identified a pathway originating from the extracellular matrix that signaled via integrin/BRAF/TAK1/ERK/ETv4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion.These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer.

关键词： PD-L1 super-enhancer ETv4 ERK αvβ3 integrin BRAF TAK1

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