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Erschienen in: Gastric Cancer 2/2016

01.04.2016 | Original Article

Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection

verfasst von: Shohei Eto, Kozo Yoshikawa, Masaaki Nishi, Jun Higashijima, Takuya Tokunaga, Toshihiro Nakao, Hideya Kashihara, Chie Takasu, Takashi Iwata, Mitsuo Shimada

Erschienen in: Gastric Cancer | Ausgabe 2/2016

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Abstract

Background

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 downregulate T cell activation and are related to immune tolerance. The aim of this study was to clarify the significance of PD-1 and PD-L1 expression and to analyze the relationships among PD-1, PD-L1, and Foxp3 expression in gastric cancer.

Methods

A total of 105 patients who underwent curative gastrectomy for stage II/III gastric cancer were included in this study. PD-1, PD-L1, and Foxp3 expression were examined by immunohistochemistry and related to prognostic factors by univariate and multivariate analyses.

Results

PD-1 expression was correlated with both PD-L1 and Foxp3 expression. Disease-free survival (DFS) was significantly poorer in PD-1-positive patients than in PD-1-negative patients (3-year DFS, 36.1 % vs. 64.7 %, respectively; p < 0.05). Overall survival also tended to be poorer in PD-L1-positive patients than in PD-L1-negative patients. Univariate analysis identified sex, T factor, lymphatic invasion, and PD-1 positivity as significant predictors of poor DFS. Multivariate analysis confirmed male sex, lymphatic invasion, and positive PD-1 expression as independent prognostic indicators.

Conclusions

PD-1 expression is associated with a poor prognosis and is correlated with PD-L1 and Foxp3 expression in patients with gastric cancer.
Literatur
1.
Zurück zum Zitat Ahmad M, Rees RC, Ali SA. Escape from immunotherapy: possible mechanisms that influence tumor regression/progression. Cancer Immunol Immunother. 2004;53(10):844–54.CrossRefPubMed Ahmad M, Rees RC, Ali SA. Escape from immunotherapy: possible mechanisms that influence tumor regression/progression. Cancer Immunol Immunother. 2004;53(10):844–54.CrossRefPubMed
2.
Zurück zum Zitat Rivoltini L, Canese P, Huber V, Iero M, Pilla L, Valenti R, et al. Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control? Expert Opinion Biol Ther. 2005;5(4):463–76.CrossRef Rivoltini L, Canese P, Huber V, Iero M, Pilla L, Valenti R, et al. Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control? Expert Opinion Biol Ther. 2005;5(4):463–76.CrossRef
3.
Zurück zum Zitat Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.PubMedPubMedCentral Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.PubMedPubMedCentral
4.
Zurück zum Zitat Cao Y, Zhang L, Ritprajak P, Tsushima F, Youngnak-Piboonratanakit P, Kamimura Y, et al. Immunoregulatory molecule B7-H1 (CD274) contributes to skin carcinogenesis. Cancer Res. 2011;71(14):4737–41. Cao Y, Zhang L, Ritprajak P, Tsushima F, Youngnak-Piboonratanakit P, Kamimura Y, et al. Immunoregulatory molecule B7-H1 (CD274) contributes to skin carcinogenesis. Cancer Res. 2011;71(14):4737–41.
5.
Zurück zum Zitat Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol. 2003;33:2706–16.CrossRefPubMed Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol. 2003;33:2706–16.CrossRefPubMed
7.
8.
Zurück zum Zitat Muenst S, Soysal SD, Gao F, et al. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2013;139(3):667–76.CrossRefPubMed Muenst S, Soysal SD, Gao F, et al. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2013;139(3):667–76.CrossRefPubMed
9.
Zurück zum Zitat Flies DB, Chen L. The new B7s: playing a pivotal role in tumor immunity. J Immunother. 2007;30:251–60.CrossRefPubMed Flies DB, Chen L. The new B7s: playing a pivotal role in tumor immunity. J Immunother. 2007;30:251–60.CrossRefPubMed
10.
Zurück zum Zitat Droeser R, Zlobec I, Kilic E, Güth U, Heberer M, Spagnoli G, et al. Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers. BMC Cancer. 2012;3(12):134.CrossRef Droeser R, Zlobec I, Kilic E, Güth U, Heberer M, Spagnoli G, et al. Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers. BMC Cancer. 2012;3(12):134.CrossRef
11.
Zurück zum Zitat Flammiger A, Weisbach L, Huland H, et al. High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer. Eur J Cancer. 2013;49(6):1273–9.CrossRefPubMed Flammiger A, Weisbach L, Huland H, et al. High tissue density of FOXP3+ T cells is associated with clinical outcome in prostate cancer. Eur J Cancer. 2013;49(6):1273–9.CrossRefPubMed
12.
Zurück zum Zitat Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74.CrossRefPubMedPubMedCentral Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Kim JW, Nam KH, Ahn S-H, Park DJ, Kim H-H, Kim SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer. 2014. doi:10.1007/s10120-014-0440-5. Kim JW, Nam KH, Ahn S-H, Park DJ, Kim H-H, Kim SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer. 2014. doi:10.​1007/​s10120-014-0440-5.
15.
Zurück zum Zitat Saito H, Kuroda H, Matsunaga T, Osaki T, Ikeguchi M. Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer. J Surg Oncol. 2013;107(5):517–22.CrossRefPubMed Saito H, Kuroda H, Matsunaga T, Osaki T, Ikeguchi M. Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer. J Surg Oncol. 2013;107(5):517–22.CrossRefPubMed
16.
Zurück zum Zitat Douglass S, Ali S, Meeson AP, Browell D, Kirby JA. The role of FOXP3 in the development and metastatic spread of breast cancer. Cancer Metastasis Rev. 2012;31(3–4):843–54.CrossRefPubMed Douglass S, Ali S, Meeson AP, Browell D, Kirby JA. The role of FOXP3 in the development and metastatic spread of breast cancer. Cancer Metastasis Rev. 2012;31(3–4):843–54.CrossRefPubMed
17.
Zurück zum Zitat Han Y, Yang Y, Chen Z, Jiang Z, Gu Y, Liu Y, et al. Human hepatocellular carcinoma-infiltrating CD4+CD69+Foxp3− regulatory T cell suppresses T cell response via membrane-bound TGF-β1. J Mol Med (Berl). 2014;92(5):539–50.CrossRefPubMed Han Y, Yang Y, Chen Z, Jiang Z, Gu Y, Liu Y, et al. Human hepatocellular carcinoma-infiltrating CD4+CD69+Foxp3 regulatory T cell suppresses T cell response via membrane-bound TGF-β1. J Mol Med (Berl). 2014;92(5):539–50.CrossRefPubMed
18.
Zurück zum Zitat Bodhankar S, Vandenbark AA, Offner H. Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17β-oestradiol-receptor-positive B cells that up-regulate PD-1 on CD4+ Foxp3+ regulatory T cells. Immunology. 2012;137(4):282–93.CrossRefPubMedPubMedCentral Bodhankar S, Vandenbark AA, Offner H. Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17β-oestradiol-receptor-positive B cells that up-regulate PD-1 on CD4+ Foxp3+ regulatory T cells. Immunology. 2012;137(4):282–93.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Sun S, Fei X, Mao Y, Wang X, Garfield DH, Huang O, et al. PD-1(+) immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunol Immunother. 2014;63(4):395–406.CrossRefPubMed Sun S, Fei X, Mao Y, Wang X, Garfield DH, Huang O, et al. PD-1(+) immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunol Immunother. 2014;63(4):395–406.CrossRefPubMed
20.
Zurück zum Zitat Merelli B, Massi D, Cattaneo L, Mandala M. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol. 2014;89:140–65.CrossRefPubMed Merelli B, Massi D, Cattaneo L, Mandala M. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol. 2014;89:140–65.CrossRefPubMed
21.
Zurück zum Zitat Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.
22.
Zurück zum Zitat Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.
23.
Zurück zum Zitat Robert C, Thomas L, Bondarenko I, O’Day S, MD JW, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.CrossRefPubMed Robert C, Thomas L, Bondarenko I, O’Day S, MD JW, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.CrossRefPubMed
24.
Zurück zum Zitat Wei H, Zhao L, Li W. Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin. PLoS One. 2013;19;8(12):e84927. Wei H, Zhao L, Li W. Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin. PLoS One. 2013;19;8(12):e84927.
Metadaten
Titel
Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection
verfasst von
Shohei Eto
Kozo Yoshikawa
Masaaki Nishi
Jun Higashijima
Takuya Tokunaga
Toshihiro Nakao
Hideya Kashihara
Chie Takasu
Takashi Iwata
Mitsuo Shimada
Publikationsdatum
01.04.2016
Verlag
Springer Japan
Erschienen in
Gastric Cancer / Ausgabe 2/2016
Print ISSN: 1436-3291
Elektronische ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-015-0519-7

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