CD47 expression in Epstein-Barr virus-associated gastric carcinoma: coexistence with tumor immunity lowering the ratio of CD8+/Foxp3+ T cells

被引：15

作者：

Abe, Hiroyuki ^{[1
]}

Saito, Ruri ^{[2
,3
]}

Ichimura, Takashi ^{[2
,4
]}

Iwasaki, Akiko ^{[2
]}

Yamazawa, Sho ^{[2
]}

Shinozaki-Ushiku, Aya ^{[1
]}

Morikawa, Teppei ^{[1
]}

Ushiku, Tetsuo ^{[1
]}

Yamashita, Hiroharu ^{[5
]}

Seto, Yasuyuki ^{[5
]}

Fukayama, Masashi ^{[1
,2
]}

机构：

[1] Univ Tokyo Hosp, Dept Pathol, Tokyo, Japan

[2] Univ Tokyo, Grad Sch Med, Dept Pathol, Tokyo, Japan

[3] Teikyo Univ, Sch Med, Dept Pathol, Tokyo, Japan

[4] Japanese Fdn Canc Res, Canc Inst Hosp, Dept Chemotherapy, Gastroenterol Ctr,Gastroenterol Internal Med, Tokyo, Japan

[5] Univ Tokyo, Grad Sch Med, Dept Gastrointestinal Surg, Tokyo, Japan

来源：

VIRCHOWS ARCHIV | 2018年 / 472卷 / 04期

基金：

日本学术振兴会;

关键词：

Epstein-Barr virus; Gastric carcinoma; CD47; CD8; Foxp3; Tumor immunity; ADVERSE PROGNOSTIC-FACTOR; PROTEIN-ALPHA; THERAPEUTIC TARGET; HODGKIN-LYMPHOMA; DENDRITIC CELLS; BREAST-CANCER; STEM-CELLS; PD-L1; PHAGOCYTOSIS; MICROENVIRONMENT;

D O I：

10.1007/s00428-018-2332-2

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) frequently harbors dense lymphocytic infiltration, suggesting a specific microenvironment allowing coexistence with tumor immunity. CD47, which mediates the "do not eat me" signal in innate immunity, is also important in adaptive anti-tumor immunity. We investigated the significance of CD47 in EBVaGC compared with EBV-negative gastric cancer and the correlation with various immune cells. By immunohistochemistry of CD47, high, low, and negative expression was observed in 24, 63, and 12% of EBVaGC (n = 41), while 11, 49, and 39% of EBV-negative gastric cancer (n = 262), respectively, indicating that high expression of CD47 in cancer cells was significantly frequent and increased in EBVaGC (P = 0.043). In contrast to EBV-negative gastric carcinoma in which no significant correlation was observed between CD47 and survival, high expression of CD47 correlated significantly with worse disease-specific survival (P = 0.011) and overall survival (P = 0.013) in EBVaGC. To further clarify the role of CD47 expression in EBVaGC, digital image analysis of immune cell infiltration revealed that high CD47 expression was correlated with a lower ratio of CD8(+)/Foxp3(+) T cells (P = 0.021), a sensitive indicator of tumor immunity. Thus, CD47 lowers anti-tumor immunity in EBVaGC by finely tuning profile of infiltrating T cells, suggesting that CD47 is an additional target for cancer immunotherapy against this virus-driven gastric cancer.

引用

页码：643 / 651

页数：9

共 32 条

[1] In Epstein-Barr virus-associated gastric carcinoma a high density of CD66b-positive tumor-associated neutrophils is associated with intestinal-type histology and low frequency of lymph node metastasis [J].

Abe, Hiroyuki ;

Morikawa, Teppei ;

Saito, Ruri ;

Yamashita, Hiroharu ;

Seto, Yasuyuki ;

Fukayama, Masashi .

VIRCHOWS ARCHIV, 2016, 468 (05) :539-548

[2] Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations [J].

Abe, Hiroyuki ;

Kaneda, Atsushi ;

Fukayama, Masashi .

PATHOBIOLOGY, 2015, 82 (05) :212-223

[3] Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer [J].

Asano, Y. ;

Kashiwagi, S. ;

Goto, W. ;

Kurata, K. ;

Noda, S. ;

Takashima, T. ;

Onoda, N. ;

Tanaka, S. ;

Ohsawa, M. ;

Hirakawa, K. .

BRITISH JOURNAL OF SURGERY, 2016, 103 (07) :845-854

[4] Comprehensive molecular characterization of gastric adenocarcinoma [J].

Bass, Adam J. ;

Thorsson, Vesteinn ;

Shmulevich, Ilya ;

Reynolds, Sheila M. ;

Miller, Michael ;

Bernard, Brady ;

Hinoue, Toshinori ;

Laird, Peter W. ;

Curtis, Christina ;

Shen, Hui ;

Weisenberger, Daniel J. ;

Schultz, Nikolaus ;

Shen, Ronglai ;

Weinhold, Nils ;

Keiser, David P. ;

Bowlby, Reanne ;

Sipahimalani, Payal ;

Cherniack, Andrew D. ;

Getz, Gad ;

Liu, Yingchun ;

Noble, Michael S. ;

Pedamallu, Chandra ;

Sougnez, Carrie ;

Taylor-Weiner, Amaro ;

Akbani, Rehan ;

Lee, Ju-Seog ;

Liu, Wenbin ;

Mills, Gordon B. ;

Yang, Da ;

Zhang, Wei ;

Pantazi, Angeliki ;

Parfenov, Michael ;

Gulley, Margaret ;

Piazuelo, M. Blanca ;

Schneider, Barbara G. ;

Kim, Jihun ;

Boussioutas, Alex ;

Sheth, Margi ;

Demchok, John A. ;

Rabkin, Charles S. ;

Willis, Joseph E. ;

Ng, Sam ;

Garman, Katherine ;

Beer, David G. ;

Pennathur, Arjun ;

Raphael, Benjamin J. ;

Wu, Hsin-Ta ;

Odze, Robert ;

Kim, Hark K. ;

Bowen, Jay .

NATURE, 2014, 513 (7517) :202-209

[5] A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer [J].

Betancur, Paola A. ;

Abraham, Brian J. ;

Yiu, Ying Y. ;

Willingham, Stephen B. ;

Khameneh, Farnaz ;

Zarnegar, Mark ;

Kuo, Angera H. ;

McKenna, Kelly ;

Kojima, Yoko ;

Leeper, Nicholas J. ;

Ho, Po ;

Gip, Phung ;

Swigut, Tomek ;

Sherwood, Richard I. ;

Clarke, Michael F. ;

Somlo, George ;

Young, Richard A. ;

Weissman, Irving L. .

NATURE COMMUNICATIONS, 2017, 8

[6] Specific infiltration of langerin-positive dendritic cells in EBV-infected tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma [J].

Braz-Silva, Paulo Henrique ;

Vitale, Sebastien ;

Butori, Catherine ;

Guevara, Nicolas ;

Santini, Jose ;

Magalhaes, Marina ;

Hofman, Paul ;

Doglio, Alain .

INTERNATIONAL JOURNAL OF CANCER, 2011, 128 (10) :2501-2508

[7] MYC regulates the antitumor immune response through CD47 and PD-L1 [J].

Casey, Stephanie C. ;

Tong, Ling ;

Li, Yulin ;

Do, Rachel ;

Walz, Susanne ;

Fitzgerald, Kelly N. ;

Gouw, Arvin M. ;

Baylot, Virginie ;

Guetgemann, Ines ;

Eilers, Martin ;

Felsher, Dean W. .

SCIENCE, 2016, 352 (6282) :227-231

[8] The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data [J].

Cerami, Ethan ;

Gao, Jianjiong ;

Dogrusoz, Ugur ;

Gross, Benjamin E. ;

Sumer, Selcuk Onur ;

Aksoy, Buelent Arman ;

Jacobsen, Anders ;

Byrne, Caitlin J. ;

Heuer, Michael L. ;

Larsson, Erik ;

Antipin, Yevgeniy ;

Reva, Boris ;

Goldberg, Arthur P. ;

Sander, Chris ;

Schultz, Nikolaus .

CANCER DISCOVERY, 2012, 2 (05) :401-404

[9] Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma [J].

Chao, Mark P. ;

Alizadeh, Ash A. ;

Tang, Chad ;

Myklebust, June H. ;

Varghese, Bindu ;

Gill, Saar ;

Jan, Max ;

Cha, Adriel C. ;

Chan, Charles K. ;

Tan, Brent T. ;

Park, Christopher Y. ;

Zhao, Feifei ;

Kohrt, Holbrook E. ;

Malumbres, Raquel ;

Briones, Javier ;

Gascoyne, Randy D. ;

Lossos, Izidore S. ;

Levy, Ronald ;

Weissman, Irving L. ;

Majeti, Ravindra .

CELL, 2010, 142 (05) :699-713

[10] Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers [J].

Derks, Sarah ;

Liao, Xiaoyun ;

Chiaravalli, Anna M. ;

Xu, Xinsen ;

Camargo, M. Constanza ;

Solcia, Enrico ;

Sessa, Fausto ;

Fleitas, Tania ;

Freeman, Gordon J. ;

Rodig, Scott J. ;

Rabkin, Charles S. ;

Bass, Adam J. .

ONCOTARGET, 2016, 7 (22) :32925-32932

← 1 2 3 4 →