Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations

被引:95
作者
Toki, Maria I. [1 ]
Mani, Nikita [1 ]
Smithy, James W. [1 ]
Liu, Yuting [1 ]
Altan, Mehmet [2 ]
Wasserman, Brad [1 ]
Tuktamyshov, Rasikh [3 ]
Schalper, Kurt [1 ,3 ]
Syrigos, Konstantinos N. [4 ]
Rimm, David L. [1 ,3 ]
机构
[1] Yale Univ, Sch Med, Dept Pathol, BML 116,310 Cedar St,POB 208023, New Haven, CT 06520 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA
[3] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA
[4] Univ Athens, Sch Med, Sotiria Gen Hosp, Dept Med 3, Athens, Greece
关键词
EGFR; Mutation; Programmed death ligand 1; Tumor infiltrating lymphocytes; NSCLC; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; PROTEIN EXPRESSION; PD-L1; EXPRESSION; EGFR MUTATIONS; CHECKPOINT INHIBITORS; QUANTITATIVE-ANALYSIS; ANTI-PD-L1; ANTIBODY; IN-SITU;
D O I
10.1016/j.jtho.2018.09.012
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
引用
收藏
页码:1884 / 1896
页数:13
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