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. 2019 Jan;14(1):25-36.
doi: 10.1016/j.jtho.2018.09.006. Epub 2018 Sep 22.

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

Hui Yu  1 , Zhengming Chen  2 , Karla V Ballman  2 , Mark A Watson  3 , Ramaswamy Govindan  3 , Irena Lanc  3 , David G Beer  4 , Raphael Bueno  5 , Lucian R Chirieac  6 , Michael Herman Chui  7 , Guoan Chen  4 , Wilbur A Franklin  8 , David R Gandara  9 , Carlo Genova  10 , Kristine A Brovsky  1 , Mary-Beth M Joshi  11 , Daniel T Merrick  8 , William G Richards  5 , Christopher J Rivard  1 , David H Harpole  11 , Ming-Sound Tsao  7 , Adrie van Bokhoven  8 , Frances A Shepherd  7 , Fred R Hirsch  12
Affiliations

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

Hui Yu et al. J Thorac Oncol. 2019 Jan.

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.

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Conflict of interest statement

Conflicts of Interest

Dr. Ballman reports grants from NCI, during the conduct of the study.

Dr. Govindan reports personal fees from Inivata, personal fees from Pfizer, honorarium and consulting fees from Genetech, personal fees from NeoHealth, personal fees from BMS, personal fees from Nektar, outside the submitted work.

Dr. Bueno reports grants from NIH UOI SPECS II, during the conduct of the study.

Dr. Genova reports personal fees from Astra Zeneca, personal fees from Boehringer-Ingelheim, personal fees from Bristol-Myers-Squibb, personal fees from MSD, personal fees from Roche, outside the submitted work.

Dr. Tsao reports grants and personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from BMS, grants and personal fees from Pfizer, personal fees from Hoffmann La Roche/Ventana, outside the submitted work.

Dr. Shepherd reports honoraria from Merck, AstraZeneca, Roche and BMS

Dr. Hirsch is co-inventor of a University of Colorado owned patent: “EGFR IHC and- FISH as predictive biomarkers for EGFR Therapy”. Dr. Hirsch has participated in advisory boards for: BMS, Genentech/Roche, HTG, Lilly, Merck, Pfizer, Ventana. Dr. Hirsch’s laboratory has received research grants (through University of Colorado) from: Genentech, BMS, Lilly, Bayer and Clovis.

All of the other authors have nothing to disclose.

Figures

Figure 1.
Figure 1.
Forest plot of hazard ratios (HRs) for 5 clinical trials assessing the efficacy of anti- PD1/PD-L1 immunotherapy versus chemotherapy with overall survival in advanced squamous NSCLC. OS, overall survival; CI, confidence interval; mo, month; NSCLC, non-small cell lung cancer.
Figure 2.
Figure 2.
Overlap between PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (TIIC).
Figure 3.
Figure 3.
A.Correlation of PD-L1 protein expression with patient overall survival in the early stage SqCLC cohort. B. Correlation of TMB with patient overall survival in the early stage SqCLC cohort. Data evaluated for TMB high identified as ≥ median value as compared to TMB low which is identified as below the median value. C. Correlation of T-effector and IFN-γ gene signature and clinical prognosis for 208 early stage SqCLC patients. Signature high represented as γ median and low as < median. Results demonstrated no difference in prognosis by overall survival in years.
Figure 4.
Figure 4.
Correlation of TC for PD-L1 protein by TPS score with PD-L1 mRNA levels, PD-L2 mRNA levels and PD-L1 mRNA to PD-L2 mRNA. Data indicates a moderate to strong association for all comparisons (r≥0.45 and P<0.0001).
Figure 5.
Figure 5.
Comparison of PD-L1 protein expression on tumor cells, TMB level and T-effector and IFN-γ gene signature score (Number in Venn diagrams represent the number of patients in each subgroups.)
Figure 6.
Figure 6.
MOSAIC plots showing the linear Trend association. A linear trend association was determined between T-effector gene signature scores and PD-L1 expression on TIICs. Higher T-effector scores are associated with higher TIICs staining.
Figure 7.
Figure 7.
Correlation of TMB/PD-L1 TPS score with patient overall survival. Data indicates no correlation for TMB and PD-L1 protein expression with prognosis.
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