Combined Radiotherapy and Anti–PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non–Small Cell Lung Cancer Xiaomei Gong, MD, PhD, Xuefei Li,

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Combined Radiotherapy and Anti–PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non–Small Cell Lung Cancer Xiaomei Gong, MD, PhD, Xuefei Li, PhD, Tao Jiang, MD, Huikang Xie, MD, Zhengfei Zhu, MD, PhD, Fei Zhou, MD, Caicun Zhou, MD, PhD Journal of Thoracic Oncology Volume 12, Issue 7, Pages 1085-1097 (July 2017) DOI: 10.1016/j.jtho.2017.04.014 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Programmed death ligand 1 (PD-L1) expression was up-regulated in cell lines after conventionally fractionated radiotherapy. (A) Growth inhibition of the A549, A459/X, A549/DDP, PC9, PC9/R, and H520 cell lines after delivery of 2 Gy of radiation per fraction by clone formation assay. (B) The expression of PD-L1 in these six cell lines by Western blot. (C) The expression of PD-L1 after conventionally fractionated radiotherapy (0, 2, 4, and 6 Gy in 2 Gy per fraction). (D) The expression of PD-L1 was increased after 6 Gy was delivered in three fractions in vitro by flow cytometry. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Journal of Thoracic Oncology 2017 12, 1085-1097DOI: (10.1016/j.jtho.2017.04.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Down-regulating programmed death ligand 1 (PD-L1) could alleviate radiation resistance by promoting apoptosis. (A and B) Radiotherapy plus anti–PD-L1 therapy significantly inhibited cell migration in A549/X cell lines. (C) Apoptosis rates of A549, A549-si-PD-L1, A549/X, and A549X/si-PD-L1 cell lines by flow cytometry. (D) Apoptosis-related proteins of A549, A549-si-PD-L1, A549/X, and A549X/si-PD-L1 cell lines. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Journal of Thoracic Oncology 2017 12, 1085-1097DOI: (10.1016/j.jtho.2017.04.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Radiotherapy may up-regulate programmed death ligand 1 (PD-L1) through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 (STAT3) pathways. (A) The expression of PD-L1, p-AKT, p-STAT3, and nuclear factor kappa B (NF-κB) of A549/X in A549, A549-si-PD-L1, A549/X, and A549X/si-PD-L1 cell lines. (B) The expression of of E-cadherin, vimentin, Snail, and N-cadherin in A549, A549-si-PD-L1, A549/X, and A549X/si-PD-L1 cell lines. (C) The expression of PD-L1, transforming growth factor-β (TGF-β), and tripartite motif containing 21 (TRIM21) in A549, A549-si-PD-L1, A549/X, and A549X/si-PD-L1 cell lines. (D) TRIM 21 may directly bond with PD-L1 via immunoprecipitation. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Journal of Thoracic Oncology 2017 12, 1085-1097DOI: (10.1016/j.jtho.2017.04.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Radiotherapy in combination with anti–programmed death ligand 1 (PD-L1) antibody synergistically enhanced antitumor immunity by reducing the accumulation of myeloid-derived suppressor cells and tumor-infiltrating regulatory T cells and promoting the accumulation of CD8-positive T cells. (A) Radiotherapy (6 Gy delivered in three fractions, once a day) in combination with anti–PD-L1 antibody effectively enhanced the inhibition of tumor growth when compared with anti–PD-L1 alone (p < 0.01) and radiotherapy alone (p < 0.01). (B–E) The expression of PD-L1, CD8-positive T cells, tumor-infiltrating regulatory T cells (CD4 positive, Fox3p-positive), and myeloid-derived suppressor cells (LyGr-positive, CD11b-positive) in a Lewis lung cancer model treated with anti–PD-L1 alone, radiotherapy alone, anti–PD-L1 plus radiotherapy, and vehicle. Journal of Thoracic Oncology 2017 12, 1085-1097DOI: (10.1016/j.jtho.2017.04.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Two representative cases revealing the correlation between programmed death ligand 1 (PD-L1) expression and response to radiotherapy. (A) Patient A with negative PD-L1 expression (IHC 0), who achieved a partial response to radiotherapy, had accumulated CD8-positive T-cell infiltration (IHC 3), reduced tumor-infiltrating regulatory T cells (IHC 1), and myeloid-derived suppressor cells (IHC 1). (B) Patient B with PD-L1 overexpression (IHC 2), who achieved stable disease in response to radiotherapy, had reduced CD8-positive T-cell infiltration (IHC 1) and accumulated tumor-infiltrating regulatory T cells (IHC 3) and myeloid-derived suppressor cells (IHC 3). Journal of Thoracic Oncology 2017 12, 1085-1097DOI: (10.1016/j.jtho.2017.04.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions