Τίτλος:
Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Introduction: Programmed death 1/programmed death ligand 1 (PD-L1) axis inhibitors have been proven effective, especially in patients with tumors expressing PD-L1. Their clinical efficacy in patients with EGFR-activating mutations is still unclear, whereas KRAS mutations seem to be associated with good response. Methods: We used multiplexed quantitative immunofluorescence to investigate PD-L1 expression and to characterize tumor infiltrating lymphocyte (TIL) populations and their activation status in more than 150 NSCLC patients with known mutation status. Results: PD-L1 expression was significantly lower in EGFR-mutant compared to KRAS-mutant, and EGFR/KRAS wild-type (WT) tumors. KRAS mutant tumors were more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis by TIL activation status revealed that EGFR mutants had a high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present they were almost always active. Additionally, we found differences between EGFR mutation sites in CD8+ expression and the TIL activation profile. Finally, activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, whereas TIL activation was associated with higher PD-L1 only in EGFR/KRAS WT. Conclusions: Our findings show the unique immune profile of EGFR-mutant tumors. The high frequency of inactive TILs could explain the low immunotherapy response rates in these patients, whereas PD-L1 as a predictive biomarker may reflect the constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation. © 2018 International Association for the Study of Lung Cancer
Συγγραφείς:
Toki, M.I.
Mani, N.
Smithy, J.W.
Liu, Y.
Altan, M.
Wasserman, B.
Tuktamyshov, R.
Schalper, K.
Syrigos, K.N.
Rimm, D.L.
Περιοδικό:
Journal of Thoracic Oncology
Εκδότης:
HANLEY & BELFUS-ELSEVIER INC
Λέξεις-κλειδιά:
biological marker; CD200 antigen; epidermal growth factor receptor; programmed death 1 ligand 1; CD274 protein, human; EGFR protein, human; epidermal growth factor receptor; GRB2 protein, human; growth factor receptor bound protein 2; programmed death 1 ligand 1; tumor marker, aged; Article; CD4+ T lymphocyte; CD8+ T lymphocyte; cell population; cohort analysis; controlled study; drug efficacy; EGFR gene; female; gene expression; gene mutation; human; human cell; immunofluorescence; immunopathogenesis; inflammation; lung carcinogenesis; lymphocyte activation; major clinical study; male; non small cell lung cancer; oncogene K ras; priority journal; protein expression; quantitative analysis; treatment response; tumor associated leukocyte; tumor microenvironment; follow up; genetics; immunology; lung adenocarcinoma; lung tumor; metabolism; mutation; non small cell lung cancer; pathology; prognosis; squamous cell carcinoma; survival rate, Adenocarcinoma of Lung; Aged; B7-H1 Antigen; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cohort Studies; ErbB Receptors; Female; Follow-Up Studies; GRB2 Adaptor Protein; Humans; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Mutation; Prognosis; Survival Rate
DOI:
10.1016/j.jtho.2018.09.012
