PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non–Small Cell Lung Cancer Seiichi Ikeda, MSc, Tatsuro Okamoto, MD,

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PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non–Small Cell Lung Cancer Seiichi Ikeda, MSc, Tatsuro Okamoto, MD, PhD, Shinji Okano, MD, PhD, Yuichiro Umemoto, MSc, Tetsuzo Tagawa, MD, PhD, Yosuke Morodomi, MD, PhD, Mikihiro Kohno, MD, PhD, Shinichiro Shimamatsu, MD, Hirokazu Kitahara, MD, Yuzo Suzuki, MD, Takatoshi Fujishita, MD, Yoshihiko Maehara, MD, PhD Journal of Thoracic Oncology Volume 11, Issue 1, Pages 62-71 (January 2016) DOI: 10.1016/j.jtho.2015.09.010 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Survival outcomes in patients with high and low PD-L1 expression. (A) Immunohistochemical staining for PD-L1 in sections of non–small cell lung cancer (NSCLC) tissue samples embedded in paraffin (original magnification ×400). (B) Hematoxylin and eosin staining of parallel sections. Arrows in both panels indicate NSCLC tissue. Recurrence-free survival (C) and overall survival (D) rates in patients with NSCLC and high (blue lines) and low (red lines) PD-L1 expression. Numbers of patients and p values are indicated. Journal of Thoracic Oncology 2016 11, 62-71DOI: (10.1016/j.jtho.2015.09.010) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Survival outcomes in patients with and without PD-L1 amplification. (A) Quantitative polymerase chain reaction–based DNA copy number analysis of PD-L1 in 94 samples of non–small cell lung cancer. Black box indicates samples with gene amplification. Recurrence-free survival (B) and overall survival (C) rates in patients with non–small cell cancer with (blue lines) and without (red lines) PD-L1 amplification. Numbers of patients and p values are indicated. Journal of Thoracic Oncology 2016 11, 62-71DOI: (10.1016/j.jtho.2015.09.010) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Coamplification of PD-L1 and JAK2 in non–small cell lung cancer (NSCLC). (A) Relationship between PD-L1 and JAK2 copy number in five samples with PD-L1 amplification and five samples without PD-L1 amplification. (B) Single-nucleotide polymorphism–comparative genomic hybridization analysis of DNA from a primary NSCLC tumor without PD-L1 amplification (upper panel) and from a primary NSCLC tumor with PD-L1 amplification (lower panel). Quantitative polymerase chain reaction–based DNA copy number analysis of PD-L1 (C) and JAK2 (D) in lung adenocarcinoma cell lines. Human umbilical vein endothelial cells were used as a copy number control (two copies). Results are representative of three independent experiments. Journal of Thoracic Oncology 2016 11, 62-71DOI: (10.1016/j.jtho.2015.09.010) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 JAK2 and PD-L1 expression in non–small cell lung cancer cell lines harboring EGFR gene mutations. (A) Western blot analysis of JAK2 in HCC4006, 11-18, PC-9, and HCC827 cells. Glyceraldehyde-3-phosphate dehydrogenase was analyzed as a loading control. Lung adenocarcinoma cell lines were treated for 48 hours with bovine serum albumin (BSA), tumor necrosis factor-α (500 U/mL), or interferon gamma (100 U/mL). Surface (B) and whole (C) expression of PD-L1 were evaluated by flow cytometry. Results are representative of three independent experiments. Asterisks indicate statistically significant differences between HCC4006 and other cell lines (*p < 0.05 versus BSA-treated condition, **p < 0.05 versus tumor necrosis factor-α–treated condition, ***p < 0.05 versus interferon gamma–treated condition). Daggers indicate statistically significant differences between the experimental and BSA-treated cells. (†p < 0.05 versus BSA-treated condition in each cell line; n.s. indicates not significant). Journal of Thoracic Oncology 2016 11, 62-71DOI: (10.1016/j.jtho.2015.09.010) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Effects of JAK2, STAT3, and STAT1 inhibitor on surface and total expression of PD-L1 in the lung adenocarcinoma cell line HCC4006. JAK2 inhibition suppresses surface and whole expression of PD-L1 in HCC4006 cells. HCC4006 cells were treated for 48 hours with the JAK2 pharmacological inhibitor TG101348 (200 nM or 500 nM) or DMSO. Surface (A) and total (B) expression of PD-L1 were evaluated by flow cytometry. Results are representative of five independent experiments. STAT3 inhibition suppresses total expression of PD-L1 in HCC4006 cells but has no effect on surface expression of PD-L1. HCC4006 cells were treated for 48 hours with the STAT3 pharmacological inhibitor BP-1-102 (0.5 μM or 5 μM) or DMSO. Surface (C) and total (D) expression of PD-L1 were evaluated by flow cytometry. Results are representative of four independent experiments. Asterisks indicate statistically significant differences between the experimental and DMSO-treated cells (*p < 0.05, **p < 0.01, ***p < 0.001). Journal of Thoracic Oncology 2016 11, 62-71DOI: (10.1016/j.jtho.2015.09.010) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions