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Cancer Therapy: Preclinical

Clinical Significance and Therapeutic Potential of the Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer

Takeo Nomi, Masayuki Sho, Takahiro Akahori, Kaoru Hamada, Atsushi Kubo, Hiromichi Kanehiro, Shinji Nakamura, Koji Enomoto, Hideo Yagita, Miyuki Azuma and Yoshiyuki Nakajima
Takeo Nomi
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Masayuki Sho
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Takahiro Akahori
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Kaoru Hamada
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Atsushi Kubo
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Hiromichi Kanehiro
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Shinji Nakamura
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Koji Enomoto
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Hideo Yagita
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Miyuki Azuma
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Yoshiyuki Nakajima
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DOI: 10.1158/1078-0432.CCR-06-2746 Published April 2007
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  • Fig. 1.
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    Fig. 1.

    Immunohistochemical staining of human pancreatic cancer tissue for PD-L1 and PD-L2. Representative case of PD-L1–positive (A) and PD-L2–positive (C) tumor. B and D, negative controls stained with mouse immunoglobulin G. Original magnification, ×400.

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    Fig. 2.

    A, overall survival of 51 patients with pancreatic cancer in relation to tumor PD-L1 status. PD-L1–positive patients had a poorer prognosis than the PD-L1–negative patients (P = 0.016). B, overall survival of 51 patients with pancreatic cancer in relation to tumor PD-L2 status. There was no significant difference in prognosis between PD-L2–positive and PD-L2–negative patients (P = 0.297).

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    Fig. 3.

    Therapeutic efficacy of PD-L1/PD-1 blockade in murine pancreatic cancer. A, expression of PD-L1 on murine pancreatic cancer cells, PAN 02. IFN-γ stimulation for 3 d in vitro induced its high expression (>95%) as estimated by flow cytometric analysis. Dashed line, negative control; thin line, naïve PAN 02; bold line, PAN 02 stimulated with IFN-γ. B, PD-L1 or PD-1 blockade induced significant antitumor effect and inhibited tumor growth. Mice were treated with anti–PD-L1 or anti–PD-1 mAb at a dose of 0.3 mg thrice per week for 4 wk. Tumor size at 4 wk after tumor establishment: anti–PD-L1 mAb, 6.3 ± 1.0 mm, n = 5; anti–PD-1 mAb, 6.0 ± 0.8 mm, n = 5; P = 0.0087 and P = 0.0025, respectively, compared with controls (9.0 ± 0.4 mm, n = 10). Points, mean maximal tumor size; bars, SE. C, immunohistochemical staining of CD8+ T cells in tumor tissue at 4 wk after tumor establishment. Representative pictures of three mice for each treatment. PD-L1 blockade induced massive CD8+ T-cell infiltration (magnification: top right, ×100; bottom right, ×400) compared with controls (top left, ×100; bottom left, ×400). D, induction of local immune activation by PD-L1 blockade. The expressions of IFN-γ, granzyme B, and perforin were significantly higher in tumors treated with anti–PD-L1 mAb than in controls (P = 0.030, P = 0.015, and P = 0.012, respectively). Points, mean of real-time PCR data from three individual mice for each group; bars, SE.

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    Fig. 4.

    Combination of PD-L1 blockade and gemcitabine. A, gemcitabine and delayed PD-L1 blockade significantly inhibited tumor growth of pancreatic cancer. Gemcitabine was given i.p. on days 1, 4, 7, 10, and 13 at a dose of 60 μg/g. Anti–PD-L1 mAb was given at a dose of 0.3 mg on days 15, 17, 19, 22, 24, and 26. Tumor size at 4 wk after tumor establishment: gemcitabine + anti–PD-L1 mAb, 5.8 ± 0.2 mm; P = 0.0077, versus gemcitabine alone, 6.8 ± 0.2 mm; P < 0.0001, versus anti–PD-L1 mAb alone, 9.0 ± 0.3 mm. B, gemcitabine and simultaneous PD-L1 blockade had a synergistic antitumor effect and resulted in complete response in treated mice. Anti–PD-L1 mAb was given at a dose of 0.3 mg for thrice per week for 4 wk. Tumor size at 4 wk after tumor establishment: gemcitabine + anti–PD-L1 mAb, 1.2 ± 0.2 mm; P < 0.0001, versus gemcitabine alone, 6.8 ± 0.2 mm; P = 0.001, versus anti–PD-L1 mAb alone, 6.2 ± 1.0 mm. Points, mean tumor size of five mice; bars, SE.

Tables

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  • Table 1.

    One-year survival rate of 51 patients with pancreatic cancer according to clinicopathologic characteristics and tumor PD-L1 status

    Variablen (%)PD-L1 positive, n (%)PD-L1 negative, n (%)P
    Tumor status
        T11 (100)1 (ND)0 (—)ND
        T27 (42.9)3 (0)4 (75.0)0.093
        T340 (54.7)15 (40.8)25 (62.9)0.019
        T43 (54.7)1 (ND)2 (ND)ND
    Nodal status
        N015 (61.9)6 (20.0)9 (87.5)0.019
        N136 (46.2)14 (40.8)22 (50.0)0.252
    Metastatic status
        M045 (52.8)17 (33.0)28 (63.2)0.035
        M16 (33.3)3 (33.3)3 (33.3)0.486
    Pathologic stage
        Ia, Ib250.0 (0)— (2)ND (ND)
        IIa13 (64.2)6 (20.0)7 (100)0.006
        IIb29 (50.6)11 (42.4)18 (55.6)0.426
        III1 (0)0 (—)1 (ND)ND
        IV6 (33.3)3 (33.3)3 (33.3)0.486
    Total51 (50.4)20 (33.5)31 (60.3)0.016
    • Abbreviation: ND, not determined.

  • Table 2.

    Inverse correlation between tumor PD-L1 status and TILs

    PD-L1CD4
    CD8
    PositiveNegativePositiveNegative
    Positive911515
    Negative247256
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Clinical Cancer Research: 13 (7)
April 2007
Volume 13, Issue 7
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Clinical Significance and Therapeutic Potential of the Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer
Takeo Nomi, Masayuki Sho, Takahiro Akahori, Kaoru Hamada, Atsushi Kubo, Hiromichi Kanehiro, Shinji Nakamura, Koji Enomoto, Hideo Yagita, Miyuki Azuma and Yoshiyuki Nakajima
Clin Cancer Res April 1 2007 (13) (7) 2151-2157; DOI: 10.1158/1078-0432.CCR-06-2746

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Clinical Significance and Therapeutic Potential of the Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer
Takeo Nomi, Masayuki Sho, Takahiro Akahori, Kaoru Hamada, Atsushi Kubo, Hiromichi Kanehiro, Shinji Nakamura, Koji Enomoto, Hideo Yagita, Miyuki Azuma and Yoshiyuki Nakajima
Clin Cancer Res April 1 2007 (13) (7) 2151-2157; DOI: 10.1158/1078-0432.CCR-06-2746
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