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

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Abstract

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.

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References

  1. Network CGAR (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–209

    Article  Google Scholar 

  2. Abe H, Kaneda A, Fukayama M (2015) Epstein-Barr virus-associated gastric carcinoma: use of host cell machineries and somatic gene mutations. Pathobiology 82:212–223

    Article  CAS  PubMed  Google Scholar 

  3. Smyth MJ, Ngiow SF, Ribas A, Teng MW (2016) Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol 13:143–158

    Article  CAS  PubMed  Google Scholar 

  4. Saito R, Abe H, Kunita A, Yamashita H, Seto Y, Fukayama M (2017) Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1+ immune cells in Epstein-Barr virus-associated gastric cancer: the prognostic implications. Mod Pathol 30:427–439

    Article  CAS  PubMed  Google Scholar 

  5. Derks S, Liao X, Chiaravalli AM, Xu X, Camargo MC, Solcia E, Sessa F, Fleitas T, Freeman GJ, Rodig SJ, Rabkin CS, Bass AJ (2016) Abundant PD-L1 expression in Epstein-Barr virus-infected gastric cancers. Oncotarget 7:32925–32932

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ichimura T, Abe H, Morikawa T, Yamashita H, Ishikawa S, Ushiku T, Seto Y, Fukayama M (2016) Low density of CD204-positive M2-type tumor-associated macrophages in Epstein-Barr virus-associated gastric cancer: a clinicopathologic study with digital image analysis. Hum Pathol 56:74–80

    Article  PubMed  Google Scholar 

  7. Abe H, Morikawa T, Saito R, Yamashita H, Seto Y, Fukayama M (2016) 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. Virchows Arch 468:539–548

    Article  CAS  PubMed  Google Scholar 

  8. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, van Rooijen N, Weissman IL (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138:286–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang H, Tan M, Zhang S, Li X, Gao J, Zhang D, Hao Y, Gao S, Liu J, Lin B (2015) Expression and significance of CD44, CD47 and c-met in ovarian clear cell carcinoma. Int J Mol Sci 16:3391–3404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, Zhao F, Kohrt HE, Malumbres R, Briones J, Gascoyne RD, Lossos IS, Levy R, Weissman IL, Majeti R (2010) Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142:699–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yoshida K, Tsujimoto H, Matsumura K, Kinoshita M, Takahata R, Matsumoto Y, Hiraki S, Ono S, Seki S, Yamamoto J, Hase K (2015) CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer. Cancer Med 4:1322–1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB, Seita J, Inlay MA, Weiskopf K, Miyanishi M, Weissman IL (2013) Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A 110:11103–11108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PO, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NNH, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109:6662–6667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, Esparza R, Richard C, Ramaswamy V, Remke M, Volkmer AK, Willingham S, Ponnuswami A, McCarty A, Lovelace P, Storm TA, Schubert S, Hutter G, Narayanan C, Chu P, Raabe EH, Harsh G IV, Taylor MD, Monje M, Cho YJ, Majeti R, Volkmer JP, Fisher PG, Grant G, Steinberg GK, Vogel H, Edwards M, Weissman IL, Cheshier SH (2017) Disrupting the CD47-SIRPalpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med 9:eaaf2968. https://doi.org/10.1126/scitranslmed.aaf2968

    Article  PubMed  Google Scholar 

  15. Liu X, Pu Y, Cron K, Deng L, Kline J, Frazier WA, Xu H, Peng H, Fu YX, Xu MM (2015) CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 21:1209–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioportal. Sci Signal 6:pl1

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404

    Article  PubMed  Google Scholar 

  18. Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49

    Article  CAS  PubMed  Google Scholar 

  19. Asano Y, Kashiwagi S, Goto W, Kurata K, Noda S, Takashima T, Onoda N, Tanaka S, Ohsawa M, Hirakawa K (2016) Tumour-infiltrating CD8 to Foxp3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. Br J Surg 103:845–854

    Article  CAS  PubMed  Google Scholar 

  20. Hatogai K, Kitano S, Fujii S, Kojima T, Daiko H, Nomura S, Yoshino T, Ohtsu A, Takiguchi Y, Doi T, Ochiai A (2016) Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma. Oncotarget 7:47252–47264

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48:452–458

    Article  CAS  PubMed  Google Scholar 

  22. Matlung HL, Szilagyi K, Barclay NA, van den Berg TK (2017) The CD47-SIRPalpha signaling axis as an innate immune checkpoint in cancer. Immunol Rev 276:145–164

    Article  CAS  PubMed  Google Scholar 

  23. Latour S, Tanaka H, Demeure C, Mateo V, Rubio M, Brown EJ, Maliszewski C, Lindberg FP, Oldenborg A, Ullrich A, Delespesse G, Sarfati M (2001) Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation. J Immunol 167:2547–2554

    Article  CAS  PubMed  Google Scholar 

  24. Braz-Silva PH, Vitale S, Butori C, Guevara N, Santini J, Magalhães M, Hofman P, Doglio A (2011) Specific infiltration of langerin-positive dendritic cells in EBV-infected tonsil, Hodgkin lymphoma and nasopharyngeal carcinoma. Int J Cancer 128:2501–2508

    Article  CAS  PubMed  Google Scholar 

  25. Li Z, Lai Y, Sun L, Zhang X, Liu R, Feng G, Zhou L, Jia L, Huang X, Kang Q, Lin D, Gao J, Shen L (2016) PD-L1 expression is associated with massive lymphocyte infiltration and histology in gastric cancer. Hum Pathol 55:182–189

    Article  PubMed  Google Scholar 

  26. Inaguma S, Wang Z, Lasota J, Sarlomo-Rikala M, McCue PA, Ikeda H, Miettinen M (2016) Comprehensive immunohistochemical study of programmed cell death ligand 1 (PD-L1): analysis in 5536 cases revealed consistent expression in trophoblastic tumors. Am J Surg Pathol 40:1133–1142

    Article  PubMed  PubMed Central  Google Scholar 

  27. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw AM, Baylot V, Gutgemann I, Eilers M, Felsher DW (2016) Myc regulates the antitumor immune response through CD47 and PD-L1. Science 352:227–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yu GT, Bu LL, Huang CF, Zhang WF, Chen WJ, Gutkind JS, Kulkarni AB, Sun ZJ (2015) PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. Oncotarget 6:42067–42080

    PubMed  PubMed Central  Google Scholar 

  29. Sockolosky JT, Dougan M, Ingram JR, Ho CCM, Kauke MJ, Almo SC, Ploegh HL, Garcia KC (2016) Durable antitumor responses to CD47 blockade require adaptive immune stimulation. Proc Natl Acad Sci U S A 113:E2646–E2654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao XW, van Beek EM, Schornagel K, van der Maaden H, van Houdt M, Otten MA, Finetti P, van Egmond M, Matozaki T, Kraal G, Birnbaum D, van Elsas A, Kuijpers TW, Bertucci F, van den Berg TK (2011) CD47-signal regulatory protein-alpha (SIRPalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A 108:18342–18347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Betancur PA, Abraham BJ, Yiu YY, Willingham SB, Khameneh F, Zarnegar M, Kuo AH, McKenna K, Kojima Y, Leeper NJ, Ho P, Gip P, Swigut T, Sherwood RI, Clarke MF, Somlo G, Young RA, Weissman IL (2017) A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Nat Commun 8:14802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang H, Lu H, Xiang L, Bullen JW, Zhang C, Samanta D, Gilkes DM, He J, Semenza GL (2015) HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci U S A 112:E6215–E6223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Kei Sakuma and Harumi Yamamura for excellent technical assistance.

Funding

This work was supported by a grant in aid for scientific research [KAKENHI] (grant numbers 26253021 (M.F.), 26860232 (H.A.), and 16K19074 (H.A.)) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan

    Hiroyuki Abe, Aya Shinozaki-Ushiku, Teppei Morikawa, Tetsuo Ushiku & Masashi Fukayama

  2. Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Ruri Saito, Takashi Ichimura, Akiko Iwasaki, Sho Yamazawa & Masashi Fukayama

  3. Department of Pathology, School of Medicine, Teikyo University, Tokyo, Japan

    Ruri Saito

  4. Department of Chemotherapy, Gastroenterology Center, Gastroenterological Internal Medicine, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    Takashi Ichimura

  5. Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Hiroharu Yamashita & Yasuyuki Seto

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  1. Hiroyuki Abe
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Correspondence to Masashi Fukayama.

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The study was approved by the institutional review board of the Faculty of Medicine, the University of Tokyo.

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Electronic supplementary material

Supplementary Fig. 1

CD47 expression and patient survival in EBV-negative gastric cancer. Expression of CD47 was not associated significantly with overall or disease specific survival in EBV-negative gastric cancer. (a) Disease specific survival. (b) Overall survival. (GIF 33 kb)

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Abe, H., Saito, R., Ichimura, T. et al. CD47 expression in Epstein-Barr virus-associated gastric carcinoma: coexistence with tumor immunity lowering the ratio of CD8+/Foxp3+ T cells. Virchows Arch 472, 643–651 (2018). https://doi.org/10.1007/s00428-018-2332-2

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  • DOI: https://doi.org/10.1007/s00428-018-2332-2

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