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Medical Oncology

, 36:60 | Cite as

Clinical significance of soluble forms of immune checkpoint molecules in advanced esophageal cancer

  • Juichiro Yoshida
  • Takeshi IshikawaEmail author
  • Toshifumi Doi
  • Takayuki Ota
  • Tomoyo Yasuda
  • Tetsuya Okayama
  • Naoyuki Sakamoto
  • Ken Inoue
  • Osamu Dohi
  • Naohisa Yoshida
  • Kazuhiro Kamada
  • Kazuhiko Uchiyama
  • Tomohisa Takagi
  • Hideyuki Konishi
  • Yuji Naito
  • Yoshito Itoh
Original Paper
  • 117 Downloads

Abstract

Immune checkpoint molecules are expressed on cancer cells and regulate tumor immunity by binding to ligands on immune cells. Although soluble forms of immune checkpoint molecules have been detected in the blood of patients with some types of tumors, their roles have not been fully elucidated. Soluble PD-L1, PD-1, CD155, LAG3, and CD226 (sPD-L1, sPD-1, sCD155, sLAG3, and sCD226, respectively) were measured in the sera of 47 patients with advanced esophageal cancer and compared with those of 24 control subjects. Pretreatment levels of sPD-1 and sCD155 were significantly higher in the patients with cancer than in the control subjects (P = 0.023, P = 0.001). The sPD-1 levels tended to be higher in the patients with lymph node metastasis, a large tumor diameter, and higher levels of serum SCC antigen (P = 0.150, P = 0.189, and P = 0.078, respectively). However, higher levels of sCD155 were associated with a better response to chemotherapy and favorable overall survival (P = 0.111 and P = 0.068, respectively). After 2 courses of chemotherapy, the levels of sCD155 and sCD226 were significantly increased (P < 0.001 and P = 0.002, respectively). Moreover, the increase in sCD226 during chemotherapy was associated with poor treatment response (P = 0.019). sPD-1 levels are possibly dependent on the tumor aggressiveness of the esophageal cancer. Furthermore, the pretreatment levels of sCD155 and kinetic change of sCD226 after chemotherapy may be used as biomarkers of the treatment response and prognosis in patients with esophageal cancer.

Keywords

Esophageal cancer Soluble immune checkpoint molecules Biomarker 

Notes

Acknowledgements

This work was supported by the Kurozumi Medical Foundation and Grant-in-Aid for Scientific Research (KAKENHI C) (17K09314) from the Japan Society for the Promotion of Science (JSPS).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval and consent to participate

This study was performed with the approval of the Ethics Review Boards of Kyoto Prefectural University of Medicine (Approval No. ERB-C-150-1).

References

  1. 1.
    Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505–27.  https://doi.org/10.1001/jamaoncol.2015.0735.CrossRefPubMedGoogle Scholar
  2. 2.
    Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371(26):2499–509.  https://doi.org/10.1056/NEJMra1314530.CrossRefGoogle Scholar
  3. 3.
    Kudo T, Hamamoto Y, Kato K, Ura T, Kojima T, Tsushima T, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol. 2017;18(5):631–9.  https://doi.org/10.1016/s1470-2045(17)30181-x.CrossRefPubMedGoogle Scholar
  4. 4.
    Doi T, Piha-Paul SA, Jalal SI, Saraf S, Lunceford J, Koshiji M, et al. Safety and antitumor activity of the anti-programmed death-1 antibody pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol. 2018;36(1):61–7.CrossRefGoogle Scholar
  5. 5.
    Masson D, Jarry A, Baury B, Blanchardie P, Laboisse C, Lustenberger P, et al. Overexpression of the CD155 gene in human colorectal carcinoma. Gut. 2001;49(2):236–40.CrossRefGoogle Scholar
  6. 6.
    Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, et al. Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112). Blood. 2005;105(5):2066–73.  https://doi.org/10.1182/blood-2004-09-3548.CrossRefPubMedGoogle Scholar
  7. 7.
    El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW, et al. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res. 2007;67(18):8444–9.  https://doi.org/10.1158/0008-5472.can-06-4230.CrossRefPubMedGoogle Scholar
  8. 8.
    Castriconi R, Dondero A, Corrias MV, Lanino E, Pende D, Moretta L, et al. Natural killer cell-mediated killing of freshly isolated neuroblastoma cells: critical role of DNAX accessory molecule-1-poliovirus receptor interaction. Cancer Res. 2004;64(24):9180–4.  https://doi.org/10.1158/0008-5472.can-04-2682.CrossRefPubMedGoogle Scholar
  9. 9.
    Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. LAG-3 regulates CD8 + T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117(11):3383–92.  https://doi.org/10.1172/jci31184.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Nagato T, Ohkuri T, Ohara K, Hirata Y, Kishibe K, Komabayashi Y, et al. Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy. Cancer Immunol Immunother. 2017;66(7):877–90.  https://doi.org/10.1007/s00262-017-1987-x.CrossRefPubMedGoogle Scholar
  11. 11.
    Koike S, Horie H, Ise I, Okitsu A, Yoshida M, Iizuka N, et al. The poliovirus receptor protein is produced both as membrane-bound and secreted forms. EMBO J. 1990;9(10):3217–24.CrossRefGoogle Scholar
  12. 12.
    Baury B, Masson D, McDermott BM Jr, Jarry A, Blottiere HM, Blanchardie P, et al. Identification of secreted CD155 isoforms. Biochem Biophys Res Commun. 2003;309(1):175–82.CrossRefGoogle Scholar
  13. 13.
    Xu Z, Zhang T, Zhuang R, Zhang Y, Jia W, Song C, et al. Increased levels of soluble CD226 in sera accompanied by decreased membrane CD226 expression on peripheral blood mononuclear cells from cancer patients. BMC Immunol. 2009;10:34.  https://doi.org/10.1186/1471-2172-10-34.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Annunziato F, Manetti R, Tomasevic I, Guidizi MG, Biagiotti R, Gianno V, et al. Expression and release of LAG-3-encoded protein by human CD4 + T cells are associated with IFN-gamma production. Faseb J. 1996;10(7):769–76.CrossRefGoogle Scholar
  15. 15.
    Nielsen C, Ohm-Laursen L, Barington T, Husby S, Lillevang ST. Alternative splice variants of the human PD-1 gene. Cell Immunol. 2005;235(2):109–16.  https://doi.org/10.1016/j.cellimm.2005.07.007.CrossRefPubMedGoogle Scholar
  16. 16.
    Wan B, Nie H, Liu A, Feng G, He D, Xu R, et al. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol. 2006;177(12):8844–50.CrossRefGoogle Scholar
  17. 17.
    Chen Y, Wang Q, Shi B, Xu P, Hu Z, Bai L, et al. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1 + cell lines. Cytokine. 2011;56(2):231–8.  https://doi.org/10.1016/j.cyto.2011.06.004.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhou J, Mahoney KM, Giobbie-Hurder A, Zhao F, Lee S, Liao X, et al. Soluble PD-L1 as a biomarker in malignant melanoma treated with checkpoint blockade. Cancer Immunol Res. 2017;5(6):480–92.  https://doi.org/10.1158/2326-6066.cir-16-0329.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wang L, Wang H, Chen H, Wang WD, Chen XQ, Geng QR, et al. Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma. Oncotarget. 2015;6(38):41228–36.  https://doi.org/10.18632/oncotarget.5682.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, et al. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. 2011;17(7):1915–23.  https://doi.org/10.1158/1078-0432.ccr-10-0250.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rossille D, Gressier M, Damotte D, Maucort-Boulch D, Pangault C, Semana G, et al. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial. Leukemia. 2014;28(12):2367–75.  https://doi.org/10.1038/leu.2014.137.CrossRefPubMedGoogle Scholar
  22. 22.
    Cheng HY, Kang PJ, Chuang YH, Wang YH, Jan MC, Wu CF, et al. Circulating programmed death-1 as a marker for sustained high hepatitis B viral load and risk of hepatocellular carcinoma. PLoS ONE. 2014;9(11):e95870.  https://doi.org/10.1371/journal.pone.0095870.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    He L, Zhang G, He Y, Zhu H, Zhang H, Feng Z. Blockade of B7-H1 with sPD-1 improves immunity against murine hepatocarcinoma. Anticancer Res. 2005;25(5):3309–13.PubMedGoogle Scholar
  24. 24.
    Song MY, Park SH, Nam HJ, Choi DH, Sung YC. Enhancement of vaccine-induced primary and memory CD8(+) T-cell responses by soluble PD-1. J Immunother. 2011;34(3):297–306.  https://doi.org/10.1097/CJI.0b013e318210ed0e.CrossRefPubMedGoogle Scholar
  25. 25.
    Amancha PK, Hong JJ, Rogers K, Ansari AA, Villinger F. In vivo blockade of the programmed cell death-1 pathway using soluble recombinant PD-1-Fc enhances CD4 + and CD8 + T cell responses but has limited clinical benefit. J Immunol. 2013;191(12):6060–70.  https://doi.org/10.4049/jimmunol.1302044.CrossRefPubMedGoogle Scholar
  26. 26.
    Sorensen SF, Demuth C, Weber B, Sorensen BS, Meldgaard P. Increase in soluble PD-1 is associated with prolonged survival in patients with advanced EGFR-mutated non-small cell lung cancer treated with erlotinib. Lung Cancer. 2016;100:77–84.  https://doi.org/10.1016/j.lungcan.2016.08.001.CrossRefPubMedGoogle Scholar
  27. 27.
    Chan CJ, Andrews DM, Smyth MJ. Receptors that interact with nectin and nectin-like proteins in the immunosurveillance and immunotherapy of cancer. Curr Opin Immunol. 2012;24(2):246–51.  https://doi.org/10.1016/j.coi.2012.01.009.CrossRefPubMedGoogle Scholar
  28. 28.
    Nishiwada S, Sho M, Yasuda S, Shimada K, Yamato I, Akahori T, et al. Clinical significance of CD155 expression in human pancreatic cancer. Anticancer Res. 2015;35(4):2287–97.PubMedGoogle Scholar
  29. 29.
    Huang DW, Huang M, Lin XS, Huang Q. CD155 expression and its correlation with clinicopathologic characteristics, angiogenesis, and prognosis in human cholangiocarcinoma. OncoTargets Ther. 2017;10:3817–25.  https://doi.org/10.2147/ott.s141476.CrossRefGoogle Scholar
  30. 30.
    Nakai R, Maniwa Y, Tanaka Y, Nishio W, Yoshimura M, Okita Y, et al. Overexpression of Necl-5 correlates with unfavorable prognosis in patients with lung adenocarcinoma. Cancer Sci. 2010;101(5):1326–30.  https://doi.org/10.1111/j.1349-7006.2010.01530.x.CrossRefPubMedGoogle Scholar
  31. 31.
    Bevelacqua V, Bevelacqua Y, Candido S, Skarmoutsou E, Amoroso A, Guarneri C, et al. Nectin like-5 overexpression correlates with the malignant phenotype in cutaneous melanoma. Oncotarget. 2012;3(8):882–92.  https://doi.org/10.18632/oncotarget.594.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Qu P, Huang X, Zhou X, Lu Z, Liu F, Shi Z, et al. Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma. Histopathology. 2015;66(5):706–14.  https://doi.org/10.1111/his.12584.CrossRefPubMedGoogle Scholar
  33. 33.
    Iguchi-Manaka A, Okumura G, Kojima H, Cho Y, Hirochika R, Bando H, et al. Increased soluble CD155 in the serum of cancer patients. PLoS ONE. 2016;11(4):e0152982.  https://doi.org/10.1371/journal.pone.0152982.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol. 2015;15(4):243–54.  https://doi.org/10.1038/nri3799.CrossRefPubMedGoogle Scholar
  35. 35.
    Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity. 1996;4(6):573–81.CrossRefGoogle Scholar
  36. 36.
    Takahashi N, Sugaya M, Suga H, Oka T, Kawaguchi M, Miyagaki T, et al. Increased soluble CD226 in sera of patients with cutaneous T-cell lymphoma mediates cytotoxic activity against tumor cells via CD155. J Invest Dermatol. 2017;137(8):1766–73.  https://doi.org/10.1016/j.jid.2017.03.025.CrossRefPubMedGoogle Scholar
  37. 37.
    Tan Z, Yang H, Wen J, Luo K, Liu Q, Hu Y, et al. Clinical predictors of pathologically response after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma: long term outcomes of a phase II study. J Thorac Dis. 2018;10(9):5254–9.  https://doi.org/10.21037/jtd.2018.08.88.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Tomasello G, Petrelli F, Ghidini M, Pezzica E, Passalacqua R, Steccanella F, et al. Tumor regression grade and survival after neoadjuvant treatment in gastro-esophageal cancer: a meta-analysis of 17 published studies. Eur J Surg Oncol. 2017;43(9):1607–16.  https://doi.org/10.1016/j.ejso.2017.03.001.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Juichiro Yoshida
    • 1
  • Takeshi Ishikawa
    • 1
    • 2
    Email author
  • Toshifumi Doi
    • 1
  • Takayuki Ota
    • 1
  • Tomoyo Yasuda
    • 1
  • Tetsuya Okayama
    • 1
  • Naoyuki Sakamoto
    • 1
  • Ken Inoue
    • 1
  • Osamu Dohi
    • 1
  • Naohisa Yoshida
    • 1
  • Kazuhiro Kamada
    • 1
  • Kazuhiko Uchiyama
    • 1
  • Tomohisa Takagi
    • 1
  • Hideyuki Konishi
    • 1
  • Yuji Naito
    • 1
  • Yoshito Itoh
    • 1
  1. 1.Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  2. 2.Outpatient Oncology Unit, University HospitalKyoto Prefectural University of MedicineKyotoJapan

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