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

Marcin Kowanetz, Wei Zou, Scott N. Gettinger, Hartmut Koeppen, Mark Kockx, Peter Schmid, Edward E. Kadel, Ignacio Wistuba, Jamie Chaft, Naiyer A. Rizvi, David R. Spigel, Alexander Spira, Fred R. Hirsch, Victor Cohen, Dustin Smith, Zach Boyd, Natasha Miley, Susan Flynn, Vincent Leveque, David S. ShamesMarcus Ballinger, Simonetta Mocci, Geetha Shankar, Roel Funke, Garret Hampton, Alan Sandler, Lukas Amler, Ira Mellman, Daniel S. Chen, Priti S. Hegde

Research output: Contribution to journalArticlepeer-review

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 nonsmall cell lung cancer (NSCLC) most likely to respond to singleagent 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. PDL1 expression on IC was more prevalent and likely reflected IFN-?-induced adaptive regulation accompanied by increased tumorinfiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PDL1 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.

Original languageEnglish (US)
Pages (from-to)E10119-E10126
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number43
DOIs
StatePublished - Oct 23 2018
Externally publishedYes

Keywords

  • Atezolizumab
  • Cancer immunotherapy
  • Checkpoints
  • PD-1
  • PD-L1

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1)'. Together they form a unique fingerprint.

Cite this