MET-Oncogenic and JAK2-Inactivating Alterations Are Independent Factors That Affect Regulation of PD-L1 Expression in Lung Cancer

Abstract

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. 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.-oncogenic activation tended to associate with positive PD-L1 immunostaining, whereas mutations were correlated with negative immunostaining. In-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 ( and ) and transcripts involved in angiogenesis ( and ) and in cell proliferation. We also report recurrent inactivating mutations in that co-occur with alterations in and which prevented the induction of immunoresponse-related genes following treatment with IFNγ. 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 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..

The Emerging Role of the c-MET-HGF Axis in Non-small Cell Lung Cancer Tumor Immunology and Immunotherapy

“…PD-L1 binding with PD-1 on activated T-lymphocytes inhibits Tcell proliferation and cytokine release (22)(23)(24), thus inhibiting anti-tumor immune responses. PD-L1 expression occurs more frequently with MET activation in NSCLC (25), suggesting that besides its well-characterized direct anti-tumor effects inhibition of c-MET signaling may act indirectly to alleviate immunosuppression. Increasing PD-L1 expression correlated positively with MET gene amplification in 389 NSCLC samples (26).…”

“…Increasing PD-L1 expression correlated positively with MET gene amplification in 389 NSCLC samples (26). A separate study of 155 resected NSCLC tumor samples found MET activation was associated with PD-L1 expression and demonstrated that in NSCLC cell lines c-MET signaling directly induces PD-L1 expression (25). Aberrant c-MET activity can contribute to acquired tumor cell resistance to treatment with epidermal growth factor receptor (EGFR) targeting tyrosine kinases (TKIs) such as erlotinib (27,28).…”

“…In response to IFN-γ produced by antitumor T-cells re-invigorated by checkpoint immunotherapy, increased tumor cell expression of PD-L1 can further raise the threshold for effective anti-tumor immunity (36). Although c-MET activation induces PD-L1 expression via a pathway distinct to that used by IFN-γ and independent of JAK/ STAT activation (25), inhibition of c-MET signaling blocks PD-L1 upregulation in response to both HGF and IFN-γ (25,37). By blocking the capacity of IFN-γ to elevate PD-L1 expression c-MET inhibition may act as an effective co-treatment to increase the effectiveness of immune checkpoint blockade in patients with tumors with aberrant MET activity.…”

Tumor-Intrinsic Response to IFNγ Shapes the Tumor Microenvironment and Anti-PD-1 Response in NSCLC

“…In melanoma, increased copy number of Socs1 was found in tumors resistant to anti-CTLA therapy [30]. In human lung tumors, MET activation was associated with increased Socs1 expression and escape from immunotherapy [32]. Conversely, chemotherapeutic agents were shown to down regulate Socs1 through induction of miR-155, resulting in increased activation of CD8 + T cells [33].…”

Machine Learning-Guided Prediction of Antigen-Reactive In Silico Clonotypes Based on Changes in Clonal Abundance through Bio-Panning

“…Numerous clinical observations have demonstrated that c-Met overexpression or gene alterations play a key role in both oncogenesis and the development of drug resistance across multiple cancer types [2][3][4][5]. Furthermore, recent research suggests that the HGF-c-Met axis limits the efficacy of cancer immunotherapy by modulating immune cell function and the expression of programmed cell death ligand 1 (PD-L1) [6][7][8][9]. Despite efforts to inhibit the HGF-c-Met axis including antibodies against c-Met or HGF, c-Met tyrosine kinase inhibitors, and more, no therapeutic agent specific to the HGF-c-Met axis is clinically available.…”