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• W4361946306 abstract "<div>Abstract<p><b>Purpose:</b> The blockade of immune checkpoints such as PD-L1 and PD-1 is being exploited therapeutically in several types of malignancies. Here, we aimed to understand the contribution of the genetics of lung cancer to the ability of tumor cells to escape immunosurveillance checkpoints.</p><p><b>Experimental Design:</b> More than 150 primary non–small cell lung cancers, including pulmonary sarcomatoid carcinomas, were tested for levels of the HLA-I complex, PD-L1, tumor-infiltrating CD8⁺ lymphocytes, and alterations in main lung cancer genes. Correlations were validated in cancer cell lines using appropriate treatments to activate or inhibit selected pathways. We also performed RNA sequencing to assess changes in gene expression after these treatments.</p><p><b>Results:</b> <i>MET</i>-oncogenic activation tended to associate with positive PD-L1 immunostaining, whereas <i>STK11</i> mutations were correlated with negative immunostaining. In <i>MET</i>-altered cancer cells, MET triggered a transcriptional increase of PD-L1 that was independent of the IFNγ-mediated JAK/STAT pathway. The activation of MET also upregulated other immunosuppressive genes (<i>PDCD1LG2</i> and <i>SOCS1</i>) and transcripts involved in angiogenesis (<i>VEGFA</i> and <i>NRP1</i>) and in cell proliferation. We also report recurrent inactivating mutations in <i>JAK2</i> that co-occur with alterations in <i>MET</i> and <i>STK11,</i> which prevented the induction of immunoresponse-related genes following treatment with IFNγ.</p><p><b>Conclusions:</b> We show that MET activation promotes the expression of several negative checkpoint regulators of the immunoresponse, including PD-L1. In addition, we report inactivation of <i>JAK2</i> in lung cancer cells that prevented the response to IFNγ. These alterations are likely to facilitate tumor growth by enabling immune tolerance and may affect the response to immune checkpoint inhibitors. <i>Clin Cancer Res; 24(18); 4579–87. ©2018 AACR</i>.</p></div>" @default.
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• W4361946306 date "2023-03-31" @default.
• W4361946306 modified "2023-10-17" @default.
• W4361946306 title "Data from <i>MET</i>-Oncogenic and <i>JAK2</i>-Inactivating Alterations Are Independent Factors That Affect Regulation of PD-L1 Expression in Lung Cancer" @default.
• W4361946306 doi "https://doi.org/10.1158/1078-0432.c.6527190" @default.
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