Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Hui Yu, Zhengming Chen, Karla V. Ballman, Mark A. Watson, Ramaswamy Govindan, Irena Lanc, David G. Beer, Raphael Bueno, Lucian R. Chirieac, Michael Herman Chui, Guoan Chen, Wilbur A. Franklin, David R Gandara, Carlo Genova, Kristine A. Brovsky, Mary Beth M. Joshi, Daniel T. Merrick, William G. Richards, Christopher J. Rivard, David H. HarpoleMing Sound Tsao, Adrie van Bokhoven, Frances A. Shepherd, Fred R. Hirsch

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Objectives: Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC. Methods: A total of 255 specimens from patients with early-stage SqCLC were identified within participating centers of the Strategic Partnering to Evaluate Cancer Signatures program. PD-L1 protein expression by immunohistochemistry was evaluated by using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer (Dako, Carpinteria, CA). Tumor mutation burden (TMB) was calculated on the basis of data from targeted genome sequencing. The T-effector and interferon gamma (IFN-γ) gene signature was determined from Affymetrix gene chip data (Affymetrix, Santa Clara, CA) from frozen specimens. Results: The prevalence of PD-L1 expression was 9.8% at a tumor proportion score cutoff of at least 50%. PD-L1 mRNA and programmed cell death 1 ligand 2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells. PD-L1 protein expression on tumor-infiltrating immune cells was correlated with the T-effector and IFN-γ gene signature (p < 0.001), but not with TMB. For TCs, all of these biomarkers were independent of each other and neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes. Conclusions: Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the cohort with early-stage SqCLC found them to be independent of each other, and none was associated with overall survival. Our results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on TCs and an adaptive mechanism on immune cells.

Original languageEnglish (US)
JournalJournal of Thoracic Oncology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Tumor Burden
Squamous Cell Carcinoma
Ligands
Lung
Mutation
Genes
Neoplasms
Neoadjuvant Therapy
Proteins
CD274 Antigen
Immunotherapy
Biomarkers
Messenger RNA
Oligonucleotide Array Sequence Analysis
Transcriptome
Interferon-gamma
Cell Death

Keywords

  • Early-stage squamous cell lung cancer
  • Immune gene signature
  • PD-L1 expression
  • Prognosis
  • Tumor mutation burden

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma. / Yu, Hui; Chen, Zhengming; Ballman, Karla V.; Watson, Mark A.; Govindan, Ramaswamy; Lanc, Irena; Beer, David G.; Bueno, Raphael; Chirieac, Lucian R.; Chui, Michael Herman; Chen, Guoan; Franklin, Wilbur A.; Gandara, David R; Genova, Carlo; Brovsky, Kristine A.; Joshi, Mary Beth M.; Merrick, Daniel T.; Richards, William G.; Rivard, Christopher J.; Harpole, David H.; Tsao, Ming Sound; van Bokhoven, Adrie; Shepherd, Frances A.; Hirsch, Fred R.

In: Journal of Thoracic Oncology, 01.01.2018.

Research output: Contribution to journalArticle

Yu, H, Chen, Z, Ballman, KV, Watson, MA, Govindan, R, Lanc, I, Beer, DG, Bueno, R, Chirieac, LR, Chui, MH, Chen, G, Franklin, WA, Gandara, DR, Genova, C, Brovsky, KA, Joshi, MBM, Merrick, DT, Richards, WG, Rivard, CJ, Harpole, DH, Tsao, MS, van Bokhoven, A, Shepherd, FA & Hirsch, FR 2018, 'Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma', Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2018.09.006
Yu, Hui ; Chen, Zhengming ; Ballman, Karla V. ; Watson, Mark A. ; Govindan, Ramaswamy ; Lanc, Irena ; Beer, David G. ; Bueno, Raphael ; Chirieac, Lucian R. ; Chui, Michael Herman ; Chen, Guoan ; Franklin, Wilbur A. ; Gandara, David R ; Genova, Carlo ; Brovsky, Kristine A. ; Joshi, Mary Beth M. ; Merrick, Daniel T. ; Richards, William G. ; Rivard, Christopher J. ; Harpole, David H. ; Tsao, Ming Sound ; van Bokhoven, Adrie ; Shepherd, Frances A. ; Hirsch, Fred R. / Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma. In: Journal of Thoracic Oncology. 2018.
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abstract = "Objectives: Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC. Methods: A total of 255 specimens from patients with early-stage SqCLC were identified within participating centers of the Strategic Partnering to Evaluate Cancer Signatures program. PD-L1 protein expression by immunohistochemistry was evaluated by using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer (Dako, Carpinteria, CA). Tumor mutation burden (TMB) was calculated on the basis of data from targeted genome sequencing. The T-effector and interferon gamma (IFN-γ) gene signature was determined from Affymetrix gene chip data (Affymetrix, Santa Clara, CA) from frozen specimens. Results: The prevalence of PD-L1 expression was 9.8{\%} at a tumor proportion score cutoff of at least 50{\%}. PD-L1 mRNA and programmed cell death 1 ligand 2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells. PD-L1 protein expression on tumor-infiltrating immune cells was correlated with the T-effector and IFN-γ gene signature (p < 0.001), but not with TMB. For TCs, all of these biomarkers were independent of each other and neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes. Conclusions: Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the cohort with early-stage SqCLC found them to be independent of each other, and none was associated with overall survival. Our results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on TCs and an adaptive mechanism on immune cells.",
keywords = "Early-stage squamous cell lung cancer, Immune gene signature, PD-L1 expression, Prognosis, Tumor mutation burden",
author = "Hui Yu and Zhengming Chen and Ballman, {Karla V.} and Watson, {Mark A.} and Ramaswamy Govindan and Irena Lanc and Beer, {David G.} and Raphael Bueno and Chirieac, {Lucian R.} and Chui, {Michael Herman} and Guoan Chen and Franklin, {Wilbur A.} and Gandara, {David R} and Carlo Genova and Brovsky, {Kristine A.} and Joshi, {Mary Beth M.} and Merrick, {Daniel T.} and Richards, {William G.} and Rivard, {Christopher J.} and Harpole, {David H.} and Tsao, {Ming Sound} and {van Bokhoven}, Adrie and Shepherd, {Frances A.} and Hirsch, {Fred R.}",
year = "2018",
month = "1",
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doi = "10.1016/j.jtho.2018.09.006",
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TY - JOUR

T1 - Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

AU - Yu, Hui

AU - Chen, Zhengming

AU - Ballman, Karla V.

AU - Watson, Mark A.

AU - Govindan, Ramaswamy

AU - Lanc, Irena

AU - Beer, David G.

AU - Bueno, Raphael

AU - Chirieac, Lucian R.

AU - Chui, Michael Herman

AU - Chen, Guoan

AU - Franklin, Wilbur A.

AU - Gandara, David R

AU - Genova, Carlo

AU - Brovsky, Kristine A.

AU - Joshi, Mary Beth M.

AU - Merrick, Daniel T.

AU - Richards, William G.

AU - Rivard, Christopher J.

AU - Harpole, David H.

AU - Tsao, Ming Sound

AU - van Bokhoven, Adrie

AU - Shepherd, Frances A.

AU - Hirsch, Fred R.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Objectives: Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC. Methods: A total of 255 specimens from patients with early-stage SqCLC were identified within participating centers of the Strategic Partnering to Evaluate Cancer Signatures program. PD-L1 protein expression by immunohistochemistry was evaluated by using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer (Dako, Carpinteria, CA). Tumor mutation burden (TMB) was calculated on the basis of data from targeted genome sequencing. The T-effector and interferon gamma (IFN-γ) gene signature was determined from Affymetrix gene chip data (Affymetrix, Santa Clara, CA) from frozen specimens. Results: The prevalence of PD-L1 expression was 9.8% at a tumor proportion score cutoff of at least 50%. PD-L1 mRNA and programmed cell death 1 ligand 2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells. PD-L1 protein expression on tumor-infiltrating immune cells was correlated with the T-effector and IFN-γ gene signature (p < 0.001), but not with TMB. For TCs, all of these biomarkers were independent of each other and neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes. Conclusions: Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the cohort with early-stage SqCLC found them to be independent of each other, and none was associated with overall survival. Our results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on TCs and an adaptive mechanism on immune cells.

AB - Objectives: Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC. Methods: A total of 255 specimens from patients with early-stage SqCLC were identified within participating centers of the Strategic Partnering to Evaluate Cancer Signatures program. PD-L1 protein expression by immunohistochemistry was evaluated by using the Dako PD-L1 22C3 pharmDx kit on the Dako Link 48 auto-stainer (Dako, Carpinteria, CA). Tumor mutation burden (TMB) was calculated on the basis of data from targeted genome sequencing. The T-effector and interferon gamma (IFN-γ) gene signature was determined from Affymetrix gene chip data (Affymetrix, Santa Clara, CA) from frozen specimens. Results: The prevalence of PD-L1 expression was 9.8% at a tumor proportion score cutoff of at least 50%. PD-L1 mRNA and programmed cell death 1 ligand 2 mRNA positively correlated with PD-L1 protein expression on tumor cells (TCs) and tumor-infiltrating immune cells. PD-L1 protein expression on tumor-infiltrating immune cells was correlated with the T-effector and IFN-γ gene signature (p < 0.001), but not with TMB. For TCs, all of these biomarkers were independent of each other and neither PD-L1 protein expression, TMB, or T-effector and IFN-γ gene signatures were independently prognostic for patient outcomes. Conclusions: Evaluation of PD-L1 expression, TMB, and T-effector and IFN-γ gene signatures in the cohort with early-stage SqCLC found them to be independent of each other, and none was associated with overall survival. Our results also support the hypothesis that PD-L1 expression is regulated by an intrinsic mechanism on TCs and an adaptive mechanism on immune cells.

KW - Early-stage squamous cell lung cancer

KW - Immune gene signature

KW - PD-L1 expression

KW - Prognosis

KW - Tumor mutation burden

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