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J Thorac Oncol. 2018 Dec;13(12):1884-1896. doi: 10.1016/j.jtho.2018.09.012. Epub 2018 Sep 26.

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

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: maria.toki@yale.edu.
2
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
3
Department of Thoracic/Head &Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
6
Third Department of Medicine, University of Athens, School of Medicine, Sotiria General Hospital, Athens, Greece.

Abstract

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.

KEYWORDS:

EGFR; Mutation; NSCLC; Programmed death ligand 1; Tumor infiltrating lymphocytes

PMID:
30267840
PMCID:
PMC6251746
[Available on 2019-12-01]
DOI:
10.1016/j.jtho.2018.09.012

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