@article{3188085, title = "Quantitative Assessment of CMTM6 in the Tumor Microenvironment and Association with Response to PD-1 Pathway Blockade in Advanced-Stage Non-Small Cell Lung Cancer", author = "Zugazagoitia, Jon and Liu, Yuting and Toki, Maria and McGuire, John and and Ahmed, Fahad Shabbir and Henick, Brian S. and Gupta, Richa and and Gettinger, Scott N. and Herbst, Roy S. and Schalper, Kurt A. and Rimm, and David L.", journal = "Journal of Thoracic Oncology", year = "2019", volume = "14", number = "12", pages = "2084-2096", publisher = "EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC", issn = "1556-0864, 1556-1380", doi = "10.1016/j.jtho.2019.09.014", keywords = "CMTM6; PD-L1; Macrophages; Immune checkpoint blockade; NSCLC", abstract = "Introduction: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) has been described as a programmed death ligand 1 (PD-L1) regulator at the protein level by modulating stability through ubiquitination. In this study, we describe the patterns of CMTM6 expression and assess its association with response to programmed cell death 1 pathway blockade in NSCLC. Methods: We used multiplexed quantitative immunofluorescence to determine the expression of CMTM6 and PD-L1 in 438 NSCLCs represented in tissue microarrays, including in two independent retrospective cohorts of immunotherapy-treated (n = 69) and non-immunotherapytreated (n = 258) patients and a third collection of EGFRand KRAS-genotyped tumors (n = 111). Results: Tumor and stromal CMTM6 expression was detected in approximately 70% of NSCLCs. CMTM6 expression was not associated with clinical features or EGFR/KRAS mutational status and showed a modest correlation with T-cell infiltration (R-2 < 0.40). We found a significant correlation between CMTM6 and PD-L1, which was higher in the stroma (R-2 = 0.51) than in tumor cells (R-2 = 0.35). In our retrospective NSCLC cohort, neither CMTM6 nor PD-L1 expression alone significantly predicted immunotherapy outcomes. However, high CMTM6 and PDL1 coexpression in the stromal and CD68 compartments (adjusted hazard ratio = 0.38, p = 0.03), but not in tumor cells (p = 0.15), was significantly associated with longer overall survival in treated patients but was not observed in the absence of immunotherapy. Conclusion: This study supports the mechanistic role for CMTM6 in stabilization of PD-L1 in patient tumors and suggests that high coexpression of CMTM6 and PD-L1, particularly in stromal immune cells (macrophages), might identify the greatest benefit from programmed cell death 1 axis blockade in NSCLC. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved." }