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

Purpose: 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.Experimental Design: 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.Results:MET-oncogenic activation tended to associate with positive PD-L1 immunostaining, whereas STK11 mutations were correlated with negative immunostaining. In MET-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 (PDCD1LG2 and SOCS1) and transcripts involved in angiogenesis (VEGFA and NRP1) and in cell proliferation. We also report recurrent inactivating mutations in JAK2 that co-occur with alterations in MET and STK11, which prevented the induction of immunoresponse-related genes following treatment with IFNγ.Conclusions: 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 JAK2 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. Clin Cancer Res; 24(18); 4579-87. ©2018 AACR.

Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers.

OBJECTIVES: To evaluate MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression in invasive lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA) of the lung, and the impact of oncogenic drivers. MATERIALS AND METHODS: MUC1, MUC2, MUC5B, MUC5AC, MUC6, TTF1 and Hnf4α immunohistochemistry was performed on surgical samples from 52 patients with IMA (n=25) or LPA (n=27). We searched for EGFR, KRAS, BRAF, and HER2 mutations and ALK, ROS1, and NRG1 rearrangements. RESULTS: MUC1, MUC2, MUC5B, MUC5AC, and MUC6 expression was detected in tumor cells in 77%, 2%, 63%, 36%, and 21% of cases, respectively. MUC1 was significantly more overexpressed in LPA. MUC5B, MUC5AC, and MUC6 were typically detected in goblet cells and overexpressed in IMA. Hnf4α-positive IMA (n=11) were TTF1-negative and typically did not expressed MUC1 and expressed MUC5AC and MUC6. Hnf4α-negative IMA (n=14) showed a reverse profile of mucins expression, with MUC1 expression and a lack of MUC5AC and MUC6 expression. EGFR-positive status was significantly associated with LPA, MUC1 expression, and no MUC5B, MUC5AC, or MUC6 expression. KRAS-positive status was significantly associated with IMA and MUC5B and MUC5AC expression. CONCLUSIONS: LPA and IMA exhibit specific mucin expression profiles, with MUC1 being associated with LPA, while MUC5B, MUC5AC, and MUC6 were associated with IMA. Hnf4α expression and EGFR and KRAS mutations may play a role in mucin expression profiles of these lung adenocarcinoma subtypes.

Clinical relevance of ROS1 rearrangements detection in advanced squamous cell carcinomas.

Non-small cell lung cancers (NSCLCs) have molecular characterization and most druggable genetic and molecular abnormalities, such as EGFR, ERBB2 and BRAF mutations, and ALK and ROS1 rearrangements, have been observed in a subset of adenocarcinomas or large cell carcinomas [1]. Even if these abnormalities are seldom detected in squamous cell carcinomas (SQCC), some rare cases of SQCC have been reported to harbor EGFR, ROS1 or ALK genetic alterations with in some cases a response to targeted therapies [2,3]. Here, we describe a patient with a SQCC harboring ROS1 rearrangement and a response to the target therapy, crizotinib.

Monocentric study of bile aspiration associated with biliary brushing performed during endoscopic retrograde cholangiopancreatography in 239 patients with symptomatic biliary stricture.

BACKGROUND: The cytologic diagnosis obtained by brushing or biopsy in malignant biliary strictures is considered to be highly specific but poorly sensitive. The diagnostic association of biliary brushing and bile exfoliate cytology has been suggested but is rarely performed in clinical practice. The objective of this study was to assess the diagnostic performance of bile aspiration associated with biliary brushing during therapeutic endoscopic retrograde cholangiopancreatography (ERCP). METHODS: From 2004 to 2009, 239 consecutive patients who underwent ERCP were included in the study. The biliary strictures were considered clinically benign in 26% of patients, uncertain in 25%, and malignant in 49%. The 298 cytologic samples collected were divided in 3 groups: bile aspiration alone (26%), biliary brushing alone (20%), and bile aspiration combined with brushing (54%). The definitive diagnosis of malignancy was obtained by biopsy, surgery, and fine-needle aspiration or was determined by an unfavorable disease course. RESULTS: The cytologic diagnoses were as follows: 149 samples were benign (50%), 114 were malignant (38%), 34 had atypia (12%), and 1 had no diagnostic value. The procedure output values were as follows: for bile aspiration alone, sensitivity was 56.4%, specificity was 93.9%, the positive predictive value (PPV) was 91.7%, and the negative predictive value (NPV) was 64.6%; for brushing alone, sensitivity was 62.5%, both specificity and the PPV were 100%, and the NPV was 73%; and, for bile aspiration and brushing combined, sensitivity was 81%, both specificity and the PPV were 100%, and the NPV was 75%. CONCLUSIONS: For patients who have symptomatic biliary stricture, bile aspiration during ERCP is a simple and safe procedure. Bile aspiration combined with brushing significantly increases the yield of cytology for malignant biliary tumors (sensitivity, 81%), particularly in cholangiocarcinomas. Cancer Cytopathol 2016;124:330-9. © 2015 American Cancer Society.