Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in nonsmall cell lung cancer

Willemijn S. M. E. Theelen, Thomas Kuilman, Katja Schulze, Wei Zou, Oscar Krijgsman, Dennis D. G. C. Peters, Sten Cornelissen, Kim Monkhorst, Pranamee Sarma, Teiko Sumiyoshi, Lukas C. Amler, Stefan M. Willems, Johannes L. G. Blaauwgeers, Carel J. M. van Noesel, Daniel S. Peeper, Michel M. van den Heuvel, Marcin Kowanetz

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background In non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics. Patients and methods Archival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell 7response was determined. Results Tumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed. Conclusions These results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.
Original languageEnglish
Article numbere0216864
JournalPLoS ONE
Volume14
Issue number5
DOIs
Publication statusPublished - 2019

Cite this

Theelen, W. S. M. E., Kuilman, T., Schulze, K., Zou, W., Krijgsman, O., Peters, D. D. G. C., ... Kowanetz, M. (2019). Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in nonsmall cell lung cancer. PLoS ONE, 14(5), [e0216864]. https://doi.org/10.1371/journal.pone.0216864
Theelen, Willemijn S. M. E. ; Kuilman, Thomas ; Schulze, Katja ; Zou, Wei ; Krijgsman, Oscar ; Peters, Dennis D. G. C. ; Cornelissen, Sten ; Monkhorst, Kim ; Sarma, Pranamee ; Sumiyoshi, Teiko ; Amler, Lukas C. ; Willems, Stefan M. ; Blaauwgeers, Johannes L. G. ; van Noesel, Carel J. M. ; Peeper, Daniel S. ; van den Heuvel, Michel M. ; Kowanetz, Marcin. / Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in nonsmall cell lung cancer. In: PLoS ONE. 2019 ; Vol. 14, No. 5.
@article{9c5a0953aaff44d5b6f14b9ad14181ea,
title = "Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in nonsmall cell lung cancer",
abstract = "Background In non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics. Patients and methods Archival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell 7response was determined. Results Tumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed. Conclusions These results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.",
author = "Theelen, {Willemijn S. M. E.} and Thomas Kuilman and Katja Schulze and Wei Zou and Oscar Krijgsman and Peters, {Dennis D. G. C.} and Sten Cornelissen and Kim Monkhorst and Pranamee Sarma and Teiko Sumiyoshi and Amler, {Lukas C.} and Willems, {Stefan M.} and Blaauwgeers, {Johannes L. G.} and {van Noesel}, {Carel J. M.} and Peeper, {Daniel S.} and {van den Heuvel}, {Michel M.} and Marcin Kowanetz",
year = "2019",
doi = "10.1371/journal.pone.0216864",
language = "English",
volume = "14",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

Theelen, WSME, Kuilman, T, Schulze, K, Zou, W, Krijgsman, O, Peters, DDGC, Cornelissen, S, Monkhorst, K, Sarma, P, Sumiyoshi, T, Amler, LC, Willems, SM, Blaauwgeers, JLG, van Noesel, CJM, Peeper, DS, van den Heuvel, MM & Kowanetz, M 2019, 'Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in nonsmall cell lung cancer' PLoS ONE, vol. 14, no. 5, e0216864. https://doi.org/10.1371/journal.pone.0216864

Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in nonsmall cell lung cancer. / Theelen, Willemijn S. M. E.; Kuilman, Thomas; Schulze, Katja; Zou, Wei; Krijgsman, Oscar; Peters, Dennis D. G. C.; Cornelissen, Sten; Monkhorst, Kim; Sarma, Pranamee; Sumiyoshi, Teiko; Amler, Lukas C.; Willems, Stefan M.; Blaauwgeers, Johannes L. G.; van Noesel, Carel J. M.; Peeper, Daniel S.; van den Heuvel, Michel M.; Kowanetz, Marcin.

In: PLoS ONE, Vol. 14, No. 5, e0216864, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in nonsmall cell lung cancer

AU - Theelen, Willemijn S. M. E.

AU - Kuilman, Thomas

AU - Schulze, Katja

AU - Zou, Wei

AU - Krijgsman, Oscar

AU - Peters, Dennis D. G. C.

AU - Cornelissen, Sten

AU - Monkhorst, Kim

AU - Sarma, Pranamee

AU - Sumiyoshi, Teiko

AU - Amler, Lukas C.

AU - Willems, Stefan M.

AU - Blaauwgeers, Johannes L. G.

AU - van Noesel, Carel J. M.

AU - Peeper, Daniel S.

AU - van den Heuvel, Michel M.

AU - Kowanetz, Marcin

PY - 2019

Y1 - 2019

N2 - Background In non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics. Patients and methods Archival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell 7response was determined. Results Tumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed. Conclusions These results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.

AB - Background In non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics. Patients and methods Archival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell 7response was determined. Results Tumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed. Conclusions These results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31125352

U2 - 10.1371/journal.pone.0216864

DO - 10.1371/journal.pone.0216864

M3 - Article

VL - 14

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 5

M1 - e0216864

ER -