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Genetic and Immune Profiles of Solid Predominant Lung Adenocarcinoma Reveal Potential Immunotherapeutic Strategies  Zhong-Yi Dong, PhD, Chao Zhang, MD,

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Presentation on theme: "Genetic and Immune Profiles of Solid Predominant Lung Adenocarcinoma Reveal Potential Immunotherapeutic Strategies  Zhong-Yi Dong, PhD, Chao Zhang, MD,"— Presentation transcript:

1 Genetic and Immune Profiles of Solid Predominant Lung Adenocarcinoma Reveal Potential Immunotherapeutic Strategies  Zhong-Yi Dong, PhD, Chao Zhang, MD, Yu-Fa Li, MD, Jian Su, MMed, Zhi Xie, MMed, Si-Yang Liu, PhD, Li-Xu Yan, PhD, Zhi-Hong Chen, MMed, Xue-Ning Yang, PhD, Jun-Tao Lin, MD, Hai-Yan Tu, MD, Jin-Ji Yang, PhD, Qing Zhou, PhD, Yue-Li Sun, PhD, Wen-Zhao Zhong, PhD, Yi-Long Wu, MD  Journal of Thoracic Oncology  Volume 13, Issue 1, Pages (January 2018) DOI: /j.jtho Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

2 Figure 1 Kaplan-Meier survival curves for disease-free survival of the patients according to each architectural grade (A). Disease-free survival curves for all patients (B) and for those with stage I (C) and those with stage II to III (D) adenocarcinoma of the solid predominant subtype versus for patients with the nonsolid predominant subtypes. Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

3 Figure 2 Expression of programmed cell death ligand 1 (PD-L1) is increased in solid predominant adenocarcinomas (A). Heatmap representation of the relative mRNA expression levels of immune checkpoint mediator/effector molecules in the six histologic subtypes. The red box indicates PD-L1, the only biomarker to demonstrate increased expression in the solid subtype but decreased expression in the other five subtypes. (B) Quantitative analyses of the PD-L1 mRNA and protein expression in tumors in The Cancer Genome Atlas (TCGA) cohort according to the different histologic subtypes. (C) Representative images of PD-L1 immunostaining in the six histologic subtypes from 194 lung adenocarcinomas. (D) Comparison of PD-L1 expression between the solid and nonsolid subtypes. (E) Comparison of the combined PD-L1 and CD8 expression in the solid and nonsolid subtypes. PD-L1 expression was divided into three groups by score indicating tumor cell (TC) and immune cell (IC) expression (TC3/IC3, TC2/IC2, and TC0–1/IC0–1). CD8 expression was divided into three groups: strong (≥50%), weak (25%–49%), and negative (<25%). PD-L1–positive/CD8-positive was defined as a PD-L1 score of TC3/IC3 and a CD8 score of 50% or higher. SOL, solid; LEP, lepidic; ACI, acinar; PAP, papillary; MIP, micropapillary; MUC, mucinous; PDCD1, programmed cell death 1 gene; PDCD1LG2, programmed cell death 1 ligand 2 gene; CTLA4, cytotoxic T-lymphocyte associated protein 4 gene; VTCN1, V-set domain containing T-cell activation inhibitor 1gene; BTLA, B and T lymphocyte associated gene; CD40, CD40 molecule gene; CD80, CD80 molecule gene; CD86, CD86 molecule gene; LAG, lymphocyte activating 3 gene; TIM3, T-cell immunoglobulin mucin family member 3 gene; CD28, CD28 molecule gene; HHLA2, HERV-H LTR-associating 2 gene; Seq, sequencing; RPPA, reverse phase protein array; NS, no significace. ***P < 0.001, **P < 0.01, *P < 0.05. Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

4 Figure 3 Solid predominant adenocarcinomas show increased mutation burden and a high rate of transversion. (A) Quantitative analysis of the tumor mutational burden in different histologic subtypes in the discovery set (The Cancer Genome Atlas [TCGA] and Broad Institute database). (B) Quantitative analysis of the tumor mutational burden in different histologic subtypes in the validation set (Guangdong Lung Cancer Institute [GLCI] data). (C) Box plot showing the proportion of transversion/transition according to the indicated histologic subtypes on the basis of data from the Broad Institute database. Transversion includes GC>TA, GC>CG, AT>TA, and AT>CG. Transition includes AT>GC and GC>AT. (D) Histogram and heatmap displaying the integrated relationship between GC>TA transversion, mutation burden, smoking (pack-years), sex, and histologic subtypes based on analysis of the GLCI data. LUAD, lung adenocarcinoma. ***P < 0.001, **P < 0.01, *P < 0.05. Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

5 Figure 4 Cytotoxic immune signature and genetic mutation profiles in solid and nonsolid adenocarcinomas. (A) Heatmap depicting mRNA expression levels of T-effector cell– and interferon gamma (IFN-γ)-associated cytotoxic immune gene signature (top) and genetic mutations potentially related to tumor immunogenicity (bottom) through analysis of The Cancer Genome Atlas (TCGA) database. (B) Quantitative analysis of four key genes in the T-effector cell (granzyme B gene [GZMB] and C-C motif chemokine ligand 4 gene [CCL4]) and IFN-γ (C-X-C motif chemokine ligand 10 gene [CXCL10] and interferon gamma gene [IFNG]) gene signatures based on solid and nonsolid subtypes. (C) Estimated proportion representation of polymerase epsilon, catalytic subunit gene (POLE) mutations in solid and nonsolid subtypes. (D) Mutation frequency of EGFR, KRAS, tumor protein p53 gene (TP53), and serine/threonine kinase 11 gene (STK11) in the solid subtype compared with in the nonsolid subtype on the basis of analysis of the discovery set (the TCGA or Broad Institute database) and validation set (Guangdong Lung Cancer Institute [GLCI] data). GZMA, granzyme A gene; EOMES, eomesodermin gene; PRF1, perforin 1 gene; CCL5, C-C motif chemokine ligand 5 gene; FAS, Fas cell surface death receptor gene; CXCL9, C-X-C motif chemokine ligand 9 gene; TBX21, T-box 21 gene; GBP5, guanylate binding protein 5 gene; POLQ, DNA polymerase theta gene; PRKDC, protein kinase, DNA-activated, catalytic polypeptide gene; ATM, ATM serine/threonine kinase gene; BRCA1, BRCA1, DNA repair associated gene; BRCA2, BRCA2, DNA repair associated gene; mut, mutation; NS, no significance. ***P < 0.001, **P < 0.01, *P < 0.05. Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

6 Supplementary Figure 1 Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

7 Supplementary Figure 2 Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

8 Supplementary Figure 3 Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

9 Supplementary Figure 4 Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

10 Supplementary Figure 5 Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

11 Supplementary Figure 6 Journal of Thoracic Oncology  , 85-96DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

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