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Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10119-E10126. doi: 10.1073/pnas.1802166115. Epub 2018 Oct 8.

Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1).

Author information

1
Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080; kowanetz.marcin@gene.com mellman.ira@gene.com.
2
Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080.
3
Medical Oncology, Yale Cancer Center, New Haven, CT 06510.
4
HistoGeneX, 2610 Antwerp, Belgium.
5
Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
6
Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77054.
7
Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
8
Hematology and Oncology, Columbia University, New York, NY 10027.
9
Sarah Cannon Research Institute, Nashville, TN 37203.
10
Oncology Program, Virginia Cancer Specialists, Fairfax, VA 22031.
11
Medical Oncology, University of Colorado Cancer Center, Denver, CO 80045.
12
Oncology, Jewish General Hospital, Montreal, QC, Canada H3T 1E2.

Abstract

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

KEYWORDS:

PD-1; PD-L1; atezolizumab; cancer immunotherapy; checkpoints

PMID:
30297397
PMCID:
PMC6205493
DOI:
10.1073/pnas.1802166115
[Indexed for MEDLINE]
Free PMC Article

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