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CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy

Hiroshi Kagamu, Shigehisa Kitano, Ou Yamaguchi, Kenichi Yoshimura, Katsuhisa Horimoto, Masashi Kitazawa, Kazuhiko Fukui, Ayako Shiono, Atsuhito Mouri, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Yoshitake Murayama, Kyoichi Kaira and Kunihiko Kobayashi
Hiroshi Kagamu
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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  • For correspondence: kagamu19@saitama-med.ac.jp
Shigehisa Kitano
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
2Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
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  • ORCID record for Shigehisa Kitano
Ou Yamaguchi
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Kenichi Yoshimura
3Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan.
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Katsuhisa Horimoto
4Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan.
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Masashi Kitazawa
4Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan.
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Kazuhiko Fukui
4Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan.
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Ayako Shiono
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Atsuhito Mouri
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Fuyumi Nishihara
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Yu Miura
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Kosuke Hashimoto
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Yoshitake Murayama
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Kyoichi Kaira
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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Kunihiko Kobayashi
1Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
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DOI: 10.1158/2326-6066.CIR-19-0574 Published March 2020
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    Figure 1.

    Correlation of T-cell subpopulations with NSCLC patient response to nivolumab therapy. A, CONSORT diagram describing patients and patient samples obtained. B–D, Differences in PBMC subpopulations in responders who achieved PR or SD (n = 26) and nonresponders (n = 14) presenting disease progression by 9 weeks after nivolumab therapy. B and C, Percentages of CD62Llow cells in total populations of CD4+ and CD8+ cells, respectively. D, Percentage of CD25+FOXP3+ cells in total population of CD4+ cells. E, Prediction formula values for discovery cohort patients. The formula, X2/Y, was based on the percentages of CD62Llow cells (X) and CD25+FOXP3+ cells (Y) in the total population of CD4+ cells. F, Receiver operating characteristic curve of the formula that predicted nonresponders in the discovery cohort (n = 40). Sensitivity and specificity at the threshold value of the formula (192) were 85.7% and 100% (P < 0.0001), respectively. G, Progression-free survival curves of discovery cohort patients diagnosed as nonresponders or responders based on the threshold value of the prediction formula (192). H, OS curves of the discovery cohort. I, Prediction formula values for validation cohort patients. J, Progression-free survival curves of validation cohort patients. K, OS curves of validation cohort patients. In B–E and I, data were presented as means ± SEM, and symbols indicate values for individual patients. Statistical significance of differences was assessed using Student two-tailed t test (B–E, I) or log-rank test (G, H, J, K).

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    Figure 2.

    Correlation between CD62Llow CD4+ T cells and other T-cell subpopulations. CCR7 and CD45RA expression on gated CD8+ CD3+ cells (A) and CD4+ CD3+ cells (B) among PBMCs. Linear correlations between the percentages of CD62LlowCD4+ cells and the percentages of CCR7−CD45RA− cells (C) and CCR7+CD45RA− or CCR7+CD45RA+ cells (D) in the total population of CD4+ cells. Linear correlations between the percentages of CD62Llow CD4+ cells and the percentages of CXCR3+ CCR4− CCR6− cells (E), CXCR3− CCR4+ CCR6− cells (F), CXCR3− CCR4− CCR6+ cells (G), or CXCR5+ cells (H), respectively, in the total population of CD4+ cells. n.s., not signficant. Linear correlation between the percentages of CD62Llow CD4+ cells and the percentages of CD8+CD3+ cells (I), (effector) CCR7−CD45RA+ CD8+ cells (J), and CD62Llow CD8+ cells (K), respectively.

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    Figure 3.

    Mass cytometry and gene expression analysis of CD4+ T cells. A, Representative illustration of viSNE analysis for 10 patients for gated CD4+CD3+ cells upon unsupervised clustering according to the expression of 29 molecules (CD3, CD4, CD8, CD19, CD27, CD28, CD45RA, CD62L, CD69, CD80, CD90, CD103, CD134, CD137, CD152, CD154, CD183, CD194, CD196, CD197, CD223, CD273, CD274, CD278, CD279, T-bet, BCL-6, FOXP3, TIM-3). B, Heatmap demonstrating the average expression of CD62L, CCR7, CD45RA, CD27, T-bet, FOXP3, CXCR3, CCR4, CCR6, and PD-1 in gated CD45RA+ CCR7+, CD45RA− CCR7−, CD62Lhigh, and CD62Llow CD4+ CD3+ T cells from 10 patients. C, Comparison of CD27, T-bet, and CXCR3 gene expression between gated CD45RA− CCR7− and CD62Llow CD4+ CD3+ T cells (n = 10). The box/whisker plots indicate median, upper quantile, and lower quantile. The lines indicate upper whiskers and lower whiskers.

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    Figure 4.

    Correlation between CD62Llow CD4+ T-cell subpopulation and PD-1, LAG3, and CTLA-4 expression and dendritic cell status. Correlations using simple linear regression analysis between the percentages of CD62Llow CD4+ cells and the percentages of indicated T-cell subpopulations (n = 84 for all). A, The percentage of CD62Llow in relation to the total number of CD4+CD3+ cells as x-axis, and the percentages of PD-1+ cells in relation to the number of CD62LlowCD4+CD3+ cells as y-axis. B, The percentages of PD-1+ cells in relation to the number of CCR7− CD45RA− CD8+CD3+ cells. C, The percentages of LAG-3+ cells in relation to the number of CD62LlowCD4+CD3+ cells. D, The percentages of CTLA-4+ cells in relation to number of CD62Llow CD4+ CD3+ cells.

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    Figure 5.

    Gene expressions correlated to response to nivolumab treatment. Gene signatures were obtained by comparing gene expression data between circulating CD62Lhigh CD4+ T cells and CD62Llow CD4+ T cells from PR, SD, and PD. A, Heatmap showing the expression of the genes expressed in CD62Llow CD4+ T cells and CD62Lhigh CD4+ T cells purified from the peripheral blood of the 6 patients consisting of 2 PR, 2 SD, and 2 PD patients. The genes that were expressed significantly higher in CD62Llow CD4+ T cells or CD62Lhigh CD4+ T cells are indicated. B, Heatmap showing the expression of the genes expressed in CD62Llow CD4+ T cells compared between PR to PD, PR to SD, and PR and SD to PD. + in the table indicates significant differences in gene expression between the groups.

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    Figure 6.

    CD62Llow CD4+ T-cell subpopulation in long-term survivors versus short-term responders. A and B, Percentages of CD62LlowCD4+ T cells and prediction formula values of pretreatment samples. Long-term responders (LR): patients who showed no disease progression for > 500 days (n = 16). Short-term responders (SR): patients who initially showed PR or SD for > 9 weeks but presented disease progression in the first 500 days after nivolumab treatment (n = 34). Nonresponders (NR): patients showing disease progression by 9 weeks after nivolumab therapy (n = 52). C and D, Comparison of the percentages of CD62Llow CD4+ T cells in PBMCs from responders and nonresponders obtained before and at 4 weeks after nivolumab treatment. E and F, Percentages of CD62Llow CD4+ T cells and prediction formula values of PBMC samples from 8 patients with ongoing responses to and 6 patients showing acquired resistance to nivolumab therapy. Data are presented as the means ± SEM. Symbols indicate values for individual patients. Statistical significance of differences was assessed using one-way ANOVA with Tukey post hoc analysis (A and B), using Student two-tailed paired t test (C and D), or using Student two-tailed unpaired t test (E and F). G, ROC curve of the formula that predicted long-term responders (n = 126). Sensitivity and specificity at the threshold value of the formula (323.5) were 68.2% and 81.7% (P < 0.0001), respectively. The red line indicates the line of identity.

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  • Table 1.

    Baseline characteristics and objective response.

    Discovery cohortValidation cohort
    Patient characteristicsn = 40n = 86
    Age, years
     Median6769
     Range51–8431–85
    Sex, n (%)
     Male26 (65.0)67 (77.9)
     Female14 (35.0)19 (22.1)
    Histology, n (%)
     Squamous10 (25.0)24 (27.9)
     Nonsquamous30 (75.0)62 (72.1)
    Smoking history, n (%)
     Current or former smoker29 (72.5)68 (79.1)
     Never smoked11 (27.5)18 (20.9)
    Disease stage, n (%)
     c-stage III9 (22.5)18 (20.9)
     c-stage IV22 (55.0)55 (64.0)
     Postoperative recurrence9 (22.5)13 (15.1)
    Driver mutation status, n (%)
     Wild type33 (82.5)73 (84.9)
     EGFR (19 del or L858R)7 (17.5)12 (14.0)
     ALK0 (0)1 (1.1)
    Objective response at 9 weeks, n (%)
     CR or PR11 (27.5)12 (14.0)
     SD15 (37.5)31 (36.0)
     PD14 (35.0)43 (50.0)
    • Abbreviations: ALK, anaplastic lymphoma kinase; CR, complete response; c-stage, clinical stage; del, deletion.

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Cancer Immunology Research: 8 (3)
March 2020
Volume 8, Issue 3
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CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy
Hiroshi Kagamu, Shigehisa Kitano, Ou Yamaguchi, Kenichi Yoshimura, Katsuhisa Horimoto, Masashi Kitazawa, Kazuhiko Fukui, Ayako Shiono, Atsuhito Mouri, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Yoshitake Murayama, Kyoichi Kaira and Kunihiko Kobayashi
Cancer Immunol Res March 1 2020 (8) (3) 334-344; DOI: 10.1158/2326-6066.CIR-19-0574

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CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy
Hiroshi Kagamu, Shigehisa Kitano, Ou Yamaguchi, Kenichi Yoshimura, Katsuhisa Horimoto, Masashi Kitazawa, Kazuhiko Fukui, Ayako Shiono, Atsuhito Mouri, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Yoshitake Murayama, Kyoichi Kaira and Kunihiko Kobayashi
Cancer Immunol Res March 1 2020 (8) (3) 334-344; DOI: 10.1158/2326-6066.CIR-19-0574
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