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E. Nadal



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    PD-L1 expression and tumor microenvironment in advanced lung cancer (ID 59)

    • Event: ELCC 2018
    • Type: Proffered Paper session
    • Track:
    • Presentations: 1
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      2O - MET activation in lung cancer up-regulates PD-L1 expression independently of JAK-STAT pathway, promoting an immunosuppressive phenotype (ID 356)

      16:45 - 18:15  |  Author(s): E. Nadal

      • Abstract
      • Presentation
      • Slides

      Background:
      The ability of tumors to avoid immune surveillance has emerged as therapeutically approachable in several types of cancer, especially through the blockade of immune checkpoints such as PD-L1/PD-1. Our purpose is to determine the contribution of somatic genomic alterations in lung cancer (LC) to the capability of tumour cells to escape the immune surveillance checkpoints.

      Methods:
      The mutation status of recurrent driver genes in lung cancer (e.g. EGFR, KRAS, MET) and the expression of immune-related molecules (PD-L1, HLA-complex, and tumour infiltrating lymphocytes CD8+, TILs) were assessed in a cohort of 155 primary resected non-small cell lung cancer (NSCLC). Correlations between genomic alterations and immune markers were determined by Chi-square test and validated in genetically characterized cancer cell lines. Functional assays were performed using appropriate treatments, including IFNγ, to modulate selected pathways. RNA-Seq analysis was performed to analyse differential gene expression with these treatments.

      Results:
      MET activation, comprising MET exon 14 skipping mutations and MET amplification, was found in 3% of samples in our cohort and these tumors were more likely to have positive immunostaining (≥5%) of PD-L1 (p = 0.05), with no specific TILs CD8+ pattern. In MET altered cancer cell lines, PD-L1 was upregulated through MET activation, independently of JAK-STAT pathway. Interestingly, we reported JAK2 loss of function mutations in LC cell lines that co-occurred with MET alterations, and abrogated the response to IFNγ. RNA-Seq analysis showed that both MET activated signature (MA-Sign) and IFNγ treatment (IFN-Sign), included genes involved in negative regulation of immune response such as CD274 (PD-L1), PDCD1LG2 (PD-L2), SOCS1 and SOCS3. However, none of the pro-immune response genes commonly found in IFN-Sign were upregulated in MA-Sign.

      Conclusions:
      MET oncogenic is not mutually exclusive with JAK2 inactivating mutations in LC and promotes the intrinsic expression of several negative checkpoints of the immune response, including PD-L1. Both genetic alterations are likely to promote tumor growth by enabling immune tolerance.

      Clinical trial identification:


      Legal entity responsible for the study:
      IDIBELL

      Funding:
      Has not received any funding

      Disclosure:
      All authors have declared no conflicts of interest.

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