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A Four-Factor Immunoscore System That Predicts Clinical Outcome for Stage II/III Gastric Cancer

Ti Wen, Zhenning Wang, Yi Li, Zhi Li, Xiaofang Che, Yibo Fan, Shuo Wang, Jinglei Qu, Xianghong Yang, Kezuo Hou, Wenyang Zhou, Ling Xu, Ce Li, Jin Wang, Jing Liu, Liqun Chen, Jingdong Zhang, Xiujuan Qu and Yunpeng Liu
Ti Wen
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Zhenning Wang
2Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Yi Li
3Department of Pathology, Cancer Hospital of Liaoning Province, Dadong District, Shenyang, China.
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Zhi Li
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Xiaofang Che
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Yibo Fan
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Shuo Wang
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Jinglei Qu
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Xianghong Yang
4Department of Pathology, Shengjing Hospital of China Medical University, Heping District, Shenyang, China.
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Kezuo Hou
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Wenyang Zhou
4Department of Pathology, Shengjing Hospital of China Medical University, Heping District, Shenyang, China.
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Ling Xu
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Ce Li
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Jin Wang
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Jing Liu
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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Liqun Chen
3Department of Pathology, Cancer Hospital of Liaoning Province, Dadong District, Shenyang, China.
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Jingdong Zhang
5Department of Medical Oncology, Cancer Hospital of Liaoning Province, Dadong District, Shenyang, China.
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Xiujuan Qu
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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  • For correspondence: cmuliuyunpeng@hotmail.com xiujuanqu@yahoo.com
Yunpeng Liu
1Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Heping District, Shenyang, China.
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  • For correspondence: cmuliuyunpeng@hotmail.com xiujuanqu@yahoo.com
DOI: 10.1158/2326-6066.CIR-16-0381 Published July 2017
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    Figure 1.

    Expression of PD-L1, PD-1, and CD8 by immune cells that infiltrated tumor tissues of gastric cancer patients. Representative images of PD-L1, PD-1, and CD8 staining in immune cells from gastric cancer samples are shown at ×200 (100 μm) original magnification. Negative expression of PD-L1 (A) and PD-1 (D, E). Positive expression of PD-L1 (B) and PD-1 (F) in areas of lymphocyte aggregates. Positive expression of PD-L1 (C) and PD-1 (G) scattered in tumor tissues. CD8Less (H) and CD8More (I) infiltrated in tumor tissues from different patients.

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    Figure 2.

    Frequencies of immune marker expression in tumor-infiltrating cells by flow cytometry and in situ multicolor immunofluorescence. Flow cytometry dot plots (A–E), IHC staining from serial section (F–H), and in situ multicolor immunofluorescence staining by confocal analysis (I–M) were conducted at the same time to confirm the frequencies of these immune factors. Shown are representative data from a patient with CD8More, PD-1hi, and PD-L1+ IC expression.

  • Figure 3.
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    Figure 3.

    OS of gastric cancer patients based on the expression of immune checkpoint proteins in immune cells and the infiltration of CD8+ T cells. A and D, OS of patients grouped by expression of PD-L1 by tumor-infiltrating immune cells; B and E, OS of patients divided by high or low expression of PD-1; C and F, OS of patients grouped by expression of more or less CD8. (A, B, and C) Patients in the discovery cohort, and (D, E, and F) patients in the validation cohort. Probabilities of OS were estimated using the Kaplan–Meier method and compared using the log-rank statistic.

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    Figure 4.

    CD8 infiltration should be combined with PD-1 expression in prognostic analysis. The Kaplan–Meier curves for OS are shown for patients grouped according to the combination of CD8+ T-cell infiltration (CD8More/CD8Less) and PD-1 expression by immune cells (PD-1hi/PD-1low). A, Discovery cohort: CD8MorePD-1Low vs. CD8LessPD-1Low, P = 0.412; CD8MorePD-1Low vs. CD8MorePD-1High, P = 0.048; CD8MorePD-1Low vs. CD8LessPD-1High, P = 0.001; CD8Less PD-1Low vs. CD8MorePD-1High, P = 0.147; CD8LessPD-1Low vs. CD8LessPD-1High, P = 0.005; and CD8More PD-1High vs. CD8Less PD-1High, P = 0.216. B, Validation cohort: CD8More PD-1Low vs. CD8Less PD-1Low, P = 0.137; CD8More PD-1Low vs. CD8More PD-1High, P = 0.103; CD8More PD-1Low vs. CD8Less PD-1High, P = 0.007; CD8Less PD-1Low vs. CD8More PD-1High, P = 0.566; CD8Less PD-1Low vs. CD8Less PD-1High, P = 0.025; and CD8More PD-1High vs. CD8Less PD-1High, P = 0.235. Probabilities of OS were estimated using the Kaplan–Meier method and compared using the log-rank statistic. Tumor-infiltrating cells were isolated from gastric cancer tissues and analyzed. C, Gates used for CD3 and CD8 double-positive cells. D, Representative dot plot for CD8 and PD-1 double-positive population. E and F, representative images of overlapping CD8 and PD-1 staining in tumor serial sections from one gastric cancer sample. G, H and I–L, representative images of coexpression of CD8 and PD-1 by multicolor IHC (CD8 in red, PD-1 in purple) and in situ immunofluorescence (400 ×) staining.

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    Figure 5.

    Expression of PD-L1 by tumor cells and its correlation with CD8 expression. A, H&E staining (panel 1), and representative images of positive PD-L1 expression (panel 2) in tumor cells surrounded by tumor-infiltrating CD8+ T cells (panel 3), at × 200 (100 μm) original magnification. B, OS of patients grouped by positive or negative expression by tumor cells of PD-L1 in the discovery cohort and C, in the validation cohort. D, OS of patients grouped by the combination of tumor cell positive or negative expression PD-L1 and “more” or “less” percentages of infiltrating CD8+ T cells, in all 166 gastric cancer patients: TC PD-L1+ CD8More vs. TC PD-L1+ CD8Less, P = 0.317; TC PD-L1+ CD8More vs.TC PD-L1− CD8More, P = 0.02; TC PD-L1+ CD8More vs. TC PD-L1− CD8Less, P = 0.002; TC PD-L1+ CD8Less vs. TC PD-L1− CD8More, P = 0.104; TC PD-L1+ CD8Less vs. TC PD-L1− CD8Less, P = 0.031; TC PD-L1− CD8More vs. TC PD-L1− CD8Less, P = 0.681. Probabilities of OS were estimated using the Kaplan–Meier method and compared using the log-rank statistics.

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    Figure 6.

    Survival curves based on immunoscore system. Expression of PD-L1/PD-1 and infiltration of CD8+ T cells have separated the patients with stage II and III (P < 0.0001) score 0 vs. score 1–2 (P = 0.07), score 0 vs. score 3–5 (P < 0.0001), score 1–2 vs. score 3–5 (P < 0.0001) A; with stage II (P =0.014) score 0 vs. score 1–2 (P = 0.447), score 0 vs. score 3–5 (P = 0.098), score 1–2 vs. score 3–5 (P = 0.011) B; with stage III (P < 0.0001) score 0 vs. score 1–2 (P = 0.10), score 0 vs. score 3–5 (P = 0.001), score 1–2 vs. score 3–5 (P < 0.0001) C, into different risk subgroups. D, ROC analysis of the 5-year survival rate based on established model and TNM stage for gastric cancer patients (n = 166). AUC of score = 0.856, AUC of stage = 0.676.

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  • Table 1.

    Univariate and multivariate analysis for OS in two cohorts of gastric cancer patients

    Univariate analysisMultivariate analysis
    HR (95% CI)P valueHR (95% CI)P valueScore
    TC PD-L1
     Positive110
     Negative2.474 (1.449–4.224)0.0011.841 (1.044–3.246)0.0351
    IC PD-L1
     Negative110
     Positive1.944 (1.165–3.243)0.0113.156 (1.775–5.611)0.0000912
    IC PD-1
     Negative110
     Positive2.236 (1.405–3.559)0.0012.354 (1.437–3.859)0.0011
    CD8
     More110
     Less1.513 (0.928–2.465)0.0971.72 (1–2.96)0.051
    Lauren classification
     Intestinal type110
     Diffuse type2.099 (1.208–3.648)0.0091.747 (1.237–2.466)0.0021
     Mix2.838 (1.382–5.826)0.0041.747 (1.237–2.466)0.0021
    Differentiation
     Well1
     Moderate1.199 (0.39–3.682)0.751
     Poor2.215 (0.802–6.118)0.125
    AJCC stage
     2110
     34.778 (1.916–11.917)0.0015.496 (2.124–14.218)0.0004423
    • Abbreviations: CI, confidence interval; HR, hazard ratio; IC, immune cell; TC, tumor cell.

Additional Files

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  • Supplementary Data

    • Supplementary Data for publication - Supplementary Data for publication
    • Supplemental Figure 1 - S1. Separation of patients with the same TNM substaging into different risk subgroups by the immunoscore system.
    • Supplemental Figure 2 - S2. OS of GC patients based on the expression of PD-L2 in tumor cells.
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Cancer Immunology Research: 5 (7)
July 2017
Volume 5, Issue 7
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A Four-Factor Immunoscore System That Predicts Clinical Outcome for Stage II/III Gastric Cancer
Ti Wen, Zhenning Wang, Yi Li, Zhi Li, Xiaofang Che, Yibo Fan, Shuo Wang, Jinglei Qu, Xianghong Yang, Kezuo Hou, Wenyang Zhou, Ling Xu, Ce Li, Jin Wang, Jing Liu, Liqun Chen, Jingdong Zhang, Xiujuan Qu and Yunpeng Liu
Cancer Immunol Res July 1 2017 (5) (7) 524-534; DOI: 10.1158/2326-6066.CIR-16-0381

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A Four-Factor Immunoscore System That Predicts Clinical Outcome for Stage II/III Gastric Cancer
Ti Wen, Zhenning Wang, Yi Li, Zhi Li, Xiaofang Che, Yibo Fan, Shuo Wang, Jinglei Qu, Xianghong Yang, Kezuo Hou, Wenyang Zhou, Ling Xu, Ce Li, Jin Wang, Jing Liu, Liqun Chen, Jingdong Zhang, Xiujuan Qu and Yunpeng Liu
Cancer Immunol Res July 1 2017 (5) (7) 524-534; DOI: 10.1158/2326-6066.CIR-16-0381
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