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 journalArticle

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

Fingerprint

Non-Small Cell Lung Carcinoma
Ligands
Neoplasms
Therapeutics
MPDL3280A
T-Lymphocytes
Epigenomics
Immunity
Histology
Immunohistochemistry
Lymphocytes

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). / Kowanetz, Marcin; Zou, Wei; Gettinger, Scott N.; Koeppen, Hartmut; Kockx, Mark; Schmid, Peter; Kadel, Edward E.; Wistuba, Ignacio; Chaft, Jamie; Rizvi, Naiyer A.; Spigel, David R.; Spira, Alexander; Hirsch, Fred R.; Cohen, Victor; Smith, Dustin; Boyd, Zach; Miley, Natasha; Flynn, Susan; Leveque, Vincent; Shames, David S.; Ballinger, Marcus; Mocci, Simonetta; Shankar, Geetha; Funke, Roel; Hampton, Garret; Sandler, Alan; Amler, Lukas; Mellman, Ira; Chen, Daniel S.; Hegde, Priti S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 43, 23.10.2018, p. E10119-E10126.

Research output: Contribution to journalArticle

Kowanetz, M, Zou, W, Gettinger, SN, Koeppen, H, Kockx, M, Schmid, P, Kadel, EE, Wistuba, I, Chaft, J, Rizvi, NA, Spigel, DR, Spira, A, Hirsch, FR, Cohen, V, Smith, D, Boyd, Z, Miley, N, Flynn, S, Leveque, V, Shames, DS, Ballinger, M, Mocci, S, Shankar, G, Funke, R, Hampton, G, Sandler, A, Amler, L, Mellman, I, Chen, DS & Hegde, PS 2018, 'Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1)', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 43, pp. E10119-E10126. https://doi.org/10.1073/pnas.1802166115
Kowanetz, Marcin ; Zou, Wei ; Gettinger, Scott N. ; Koeppen, Hartmut ; Kockx, Mark ; Schmid, Peter ; Kadel, Edward E. ; Wistuba, Ignacio ; Chaft, Jamie ; Rizvi, Naiyer A. ; Spigel, David R. ; Spira, Alexander ; Hirsch, Fred R. ; Cohen, Victor ; Smith, Dustin ; Boyd, Zach ; Miley, Natasha ; Flynn, Susan ; Leveque, Vincent ; Shames, David S. ; Ballinger, Marcus ; Mocci, Simonetta ; Shankar, Geetha ; Funke, Roel ; Hampton, Garret ; Sandler, Alan ; Amler, Lukas ; Mellman, Ira ; Chen, Daniel S. ; Hegde, Priti S. / Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 43. pp. E10119-E10126.
@article{d410abb79c8a4e53b3b51791d2435a8f,
title = "Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1)",
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.",
keywords = "Atezolizumab, Cancer immunotherapy, Checkpoints, PD-1, PD-L1",
author = "Marcin Kowanetz and Wei Zou and Gettinger, {Scott N.} and Hartmut Koeppen and Mark Kockx and Peter Schmid and Kadel, {Edward E.} and Ignacio Wistuba and Jamie Chaft and Rizvi, {Naiyer A.} and Spigel, {David R.} and Alexander Spira and Hirsch, {Fred R.} and Victor Cohen and Dustin Smith and Zach Boyd and Natasha Miley and Susan Flynn and Vincent Leveque and Shames, {David S.} and Marcus Ballinger and Simonetta Mocci and Geetha Shankar and Roel Funke and Garret Hampton and Alan Sandler and Lukas Amler and Ira Mellman and Chen, {Daniel S.} and Hegde, {Priti S.}",
year = "2018",
month = "10",
day = "23",
doi = "10.1073/pnas.1802166115",
language = "English (US)",
volume = "115",
pages = "E10119--E10126",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "43",

}

TY - JOUR

T1 - Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1)

AU - Kowanetz, Marcin

AU - Zou, Wei

AU - Gettinger, Scott N.

AU - Koeppen, Hartmut

AU - Kockx, Mark

AU - Schmid, Peter

AU - Kadel, Edward E.

AU - Wistuba, Ignacio

AU - Chaft, Jamie

AU - Rizvi, Naiyer A.

AU - Spigel, David R.

AU - Spira, Alexander

AU - Hirsch, Fred R.

AU - Cohen, Victor

AU - Smith, Dustin

AU - Boyd, Zach

AU - Miley, Natasha

AU - Flynn, Susan

AU - Leveque, Vincent

AU - Shames, David S.

AU - Ballinger, Marcus

AU - Mocci, Simonetta

AU - Shankar, Geetha

AU - Funke, Roel

AU - Hampton, Garret

AU - Sandler, Alan

AU - Amler, Lukas

AU - Mellman, Ira

AU - Chen, Daniel S.

AU - Hegde, Priti S.

PY - 2018/10/23

Y1 - 2018/10/23

N2 - 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.

AB - 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.

KW - Atezolizumab

KW - Cancer immunotherapy

KW - Checkpoints

KW - PD-1

KW - PD-L1

UR - http://www.scopus.com/inward/record.url?scp=85055600353&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055600353&partnerID=8YFLogxK

U2 - 10.1073/pnas.1802166115

DO - 10.1073/pnas.1802166115

M3 - Article

C2 - 30297397

AN - SCOPUS:85055600353

VL - 115

SP - E10119-E10126

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 43

ER -