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Prognostic significance of NY-ESO-1 antigen and PIGR expression in esophageal tumors of CHP-NY-ESO-1-vaccinated patients as adjuvant therapy

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Abstract

The aim of this study was to determine the efficacy and the biomarkers of the CHP-NY-ESO-1 vaccine complexed with full-length NY-ESO-1 protein and a cholesteryl pullulan (CHP) in patients with esophageal squamous cell carcinoma (ESCC) after surgery. We conducted a randomized phase II trial. Fifty-four patients with NY-ESO-1–expressing ESCC who underwent radical surgery following cisplatin/5-fluorouracil–based neoadjuvant chemotherapy were assigned to receive either CHP-NY-ESO-1 vaccination or observation as control. Six doses of CHP-NY-ESO-1 were administered subcutaneously once every two weeks, followed by nine more doses once every four weeks. The endpoints were disease-free survival (DFS) and safety. Exploratory analysis of tumor tissues using gene-expression profiles was also performed to seek the biomarker. As there were no serious adverse events in 27 vaccinated patients, we verified the safety of the vaccine. DFS in 2 years were 56.0% and 58.3% in the vaccine arm and in the control, respectively. Twenty-four of 25 patients showed NY-ESO-1-specific IgG responses after vaccination. Analysis of intra-cohort correlations among vaccinated patients revealed that 5% or greater expression of NY-ESO-1 was a favorable factor. Comprehensive analysis of gene expression profiles revealed that the expression of the gene encoding polymeric immunoglobulin receptor (PIGR) in tumors had a significantly favorable impact on outcomes in the vaccinated cohort. The high PIGR-expressing tumors that had higher NY-ESO-1-specific IgA response tended to have favorable prognosis. These results suggest that PIGR would play a major role in tumor immunity in an antigen-specific manner during NY-ESO-1 vaccinations. The IgA response may be relevant.

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Data availability

To protect patient information in the clinical trial database, the datasets generated and/or analyzed in the present study are not publicly available, but they are available from the corresponding author on request.

Abbreviations

AUC:

Area under the curve

cGMP:

Current good manufacturing practices

CI:

Confidence interval

CHP:

Cholesteryl pullulan

CT:

Computed tomography

DFS:

Disease-free survival

EC:

Esophageal cancer

ELISA:

Enzyme-linked immunosorbent assay

ESCC:

Esophageal squamous cell carcinoma

γ-GTP:

γ-Glutamyl transpeptidase

IFN-γ :

Interferon-γ

IgA:

Immunoglobulin A

IgM:

Immunoglobulin M

IL-1:

Interleukin-1

IL-4:

Interleukin-4

MAGE-A4:

Melanoma-associated gene-A4

MHC:

Major histocompatibility complex

MRI:

Magnetic resonance imaging

NCI-CTCAE:

National Cancer Institute Common Terminology Criteria for Adverse Events

NKG2D :

NK group 2 member D

NY-ESO-1:

New York esophageal squamous cell carcinoma-1

OD:

Optical density

OS:

Overall survival

PD-1:

Programmed-cell death-1

PIGR :

Polymeric immunoglobulin receptor

PPS:

Per-protocol set

RNA:

Ribonucleic acid

ROC:

Receiver operating characteristics

TNF-α :

Tumor necrosis factor-α

UICC:

Union for International Cancer Control

UMIN:

University hospital medical information network

References

  1. Boon T (1993) Tumor antigens recognized by cytolytic T lymphocytes: present perspectives for specific immunotherapy. Int J Cancer 54:177–180. https://doi.org/10.1002/ijc.2910540202

    Article  CAS  PubMed  Google Scholar 

  2. Ferlay J, Colombet M, Soerjomataram I et al (2019) Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144:1941–1953. https://doi.org/10.1002/ijc.31937

    Article  CAS  PubMed  Google Scholar 

  3. Shapiro J, van Lanschot JJB, Hulshof MCCM et al (2015) Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 16:1090–1098. https://doi.org/10.1016/S1470-2045(15)00040-6

    Article  PubMed  Google Scholar 

  4. Ando N, Kato H, Igaki H et al (2012) A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 19:68–74. https://doi.org/10.1245/s10434-011-2049-9

    Article  PubMed  Google Scholar 

  5. Mayanagi S, Irino T, Kawakubo H, Kitagawa Y (2019) Neoadjuvant treatment strategy for locally advanced thoracic esophageal cancer. Ann Gastroenterol Surg 3:269–275. https://doi.org/10.1002/ags3.12243

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kelly RJ, Ajani JA, Kuzdzal J et al (2021) Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. New Engl J Med 384:1191–1203. https://doi.org/10.1056/NEJMoa2032125

    Article  CAS  PubMed  Google Scholar 

  7. Chen YT, Scanlan MJ, Sahin U et al (1997) A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA 94:1914–1918. https://doi.org/10.1073/pnas.94.5.1914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jungbluth AA, Chen YT, Stockert E et al (2001) Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues. Int J Cancer 92:856–860. https://doi.org/10.1002/ijc.1282

    Article  CAS  PubMed  Google Scholar 

  9. Gu XG, Schmitt M, Hiasa A et al (1998) A novel hydrophobized polysaccharide/oncoprotein complex vaccine induces in vitro and in vivo cellular and humoral immune responses against HER2- expressing murine sarcomas. Cancer Res 58:3385–3390

    CAS  PubMed  Google Scholar 

  10. Muraoka D, Harada N, Hayashi T et al (2014) Nanogel-based immunologically stealth vaccine targets macrophages in the medulla of lymph node and induces potent antitumor immunity. ACS Nano 8:9209–9218. https://doi.org/10.1021/nn502975r

    Article  CAS  PubMed  Google Scholar 

  11. Ikuta Y, Katayama N, Wang L et al (2002) Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy. Blood 99:3717–3724. https://doi.org/10.1182/blood.V99.10.3717

    Article  CAS  PubMed  Google Scholar 

  12. Kitano S, Kageyama S, Nagata Y et al (2006) HER2-specific T-cell immune responses in patients vaccinated with truncated HER2 protein complexed with nanogels of cholesteryl pullulan. Clin Cancer Res 12:7397–7405. https://doi.org/10.1158/1078-0432.CCR-06-1546

    Article  CAS  PubMed  Google Scholar 

  13. Kageyama S, Wada H, Muro K et al (2013) Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients. J Transl Med 11:246. https://doi.org/10.1186/1479-5876-11-246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Murphy R, Green S, Ritter G et al (2005) Recombinant NY-ESO-1 cancer antigen: Production and purification under cGMP conditions. Prep Biochem Biotechnol 35:119–134. https://doi.org/10.1081/PB-200054732

    Article  CAS  PubMed  Google Scholar 

  15. Akiyoshi K, Kobayashi S, Shichibe S et al (1998) Self-assembled hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs: complexation and stabilization of insulin. J Control Release 54:313–320. https://doi.org/10.1016/S0168-3659(98)00017-0

    Article  CAS  PubMed  Google Scholar 

  16. Stockert E, Jäger E, Chen Y-T et al (1998) A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp Med 187:1349–1354. https://doi.org/10.1084/jem.187.8.1349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kaetzel CS (2005) The polymeric immunoglobulin receptor: Bridging innate and adaptive immune responses at mucosal surfaces. Immunol Rev 206:83–99. https://doi.org/10.1111/j.0105-2896.2005.00278.x

    Article  CAS  PubMed  Google Scholar 

  18. Figueiredo DLA, Mamede RCM, Spagnoli GC et al (2011) High expression of cancer testis antigens MAGE-A, MAGE-C1/CT7, MAGE-C2/CT10, NY-ESO-1, and gage in advanced squamous cell carcinoma of the larynx. Head Neck 33:702–707. https://doi.org/10.1002/hed.21522

    Article  PubMed  Google Scholar 

  19. Szender JB, Papanicolau-Sengos A, Eng KH et al (2017) NY-ESO-1 expression predicts an aggressive phenotype of ovarian cancer. Gynecol Oncol 145:420–425. https://doi.org/10.1016/j.ygyno.2017.03.509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ueda S, Miyahara Y, Nagata Y, Sato E, Shiraishi T, Harada N, Ikeda H, Shiku H, Kageyama S (2018) NY-ESO-1 antigen expression and immune response are associated with poor prognosis in MAGE-A4-vaccinated patients with esophageal or head/neck squamous cell carcinoma. Oncotarget 9(89):35997–36011. https://doi.org/10.18632/oncotarget.26323

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hayashi M, Takenouchi N, Asano M et al (1997) The polymeric immunoglobulin receptor (secretory component) in a human intestinal epithelial cell line is up-regulated by interleukin-1. Immunology 92:220–225. https://doi.org/10.1046/j.1365-2567.1997.00341.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Piskurich JF, France JA, Tamer CM et al (1993) Interferon-γ induces polymeric immunoglobulin receptor mrna in human intestinal epithelial cells by a protein synthesis dependent mechanism. Mol Immunol 30:413–421. https://doi.org/10.1016/0161-5890(93)90071-I

    Article  CAS  PubMed  Google Scholar 

  23. Moon C, VanDussen KL, Miyoshi H, Stappenbeck TS (2014) Development of a primary mouse intestinal epithelial cell monolayer culture system to evaluate factors that modulate IgA transcytosis. Mucosal Immunol 7:818–828. https://doi.org/10.1038/mi.2013.98

    Article  CAS  PubMed  Google Scholar 

  24. Kumar P, Monin L, Castillo P et al (2016) Intestinal Interleukin-17 receptor signaling mediates reciprocal control of the gut microbiota and autoimmune inflammation. Immunity 44:659–671. https://doi.org/10.1016/j.immuni.2016.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fristedt R, Gaber A, Hedner C et al (2014) Expression and prognostic significance of the polymeric immunoglobulin receptor in esophageal and gastric adenocarcinoma. J Transl Med 12:83. https://doi.org/10.1186/1479-5876-12-83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fristedt R, Elebro J, Gaber A et al (2014) Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis. PLoS ONE 9:e112728. https://doi.org/10.1371/journal.pone.0112728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Biswas S, Mandal G, Payne KK et al (2021) IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature 591:464–470. https://doi.org/10.1038/s41586-020-03144-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to all the patients who took part in this study, their caregivers, and the co-medical staff, data managers, and clinical coordinators. Ms.Sahoko Sugino and Ms. Junko Nakamura (Mie University) provided technical assistance with the ELISA assay. We thank all co-workers from FIVERINGS CO., LTD. for operating this study.

Funding

The trial was supported by research funding from the Ministry of Health, Labour and Welfare, Japan between April 2011 and March 2015, and then supported by Japan Agency for Medical Research and Development (AMED) between April 2015 and March 2018 (Grant Number JP17ck0106143).

Author information

Authors and Affiliations

  1. Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Yasuhiro Nagata

  2. Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Japan

    Shinichi Kageyama, Yoshihiro Miyahara, Takashi Watanabe & Hiroshi Shiku

  3. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Takeshi Ishikawa, Satoshi Kokura & Tetsuya Okayama

  4. Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan

    Tetsuya Abe

  5. Division of Gastroenterological and General Surgery, School of Medicine, Showa University, Tokyo, Japan

    Masahiko Murakami, Koji Otsuka & Tomotake Ariyoshi

  6. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Hospital East, Kashiwa, Japan

    Takashi Kojima

  7. Department of Surgery, Nagasaki Medical Center, Omura, Japan

    Ken Taniguchi & Shinichiro Kobayashi

  8. Department of Gastroenterological Surgery, Toho University Omori Medical Center, Tokyo, Japan

    Hideaki Shimada, Satoshi Yajima & Takashi Suzuki

  9. Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Japan

    Satoshi Hirano, Takahiro Tsuchikawa & Toshiaki Shichinohe

  10. Department of Gastroenterological Surgery and Oncology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan

    Shugo Ueda

  11. Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Kengo Kanetaka & Akira Yoneda

  12. Department of Clinical Research in Tumor Immunology, Osaka University Graduate School of Medicine, Suita, Japan

    Hisashi Wada

  13. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan

    Yuichiro Doki

  14. Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan

    Hiroki Yamaue & Masahiro Katsuda

  15. Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan

    Masaki Ohi & Hiromi Yasuda

  16. Department of Surgery, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Ken Kondo & Masato Kataoka

  17. Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yasuhiro Kodera & Masahiko Koike

  18. Department of Oncologic Pathology, Mie University Graduate School of Medicine, Tsu, Japan

    Taizo Shiraishi

  19. Department of Human Science, Faculty of Human Science, Musashino University, Tokyo, Japan

    Naoki Goshima

  20. Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan

    Eriko Fukuda

  21. Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan

    Kei Yamaguchi

  22. Department of Pathology (Medical Research Center), Institute of Medical Science, Tokyo Medical University, Tokyo, Japan

    Eiichi Sato

  23. Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Hiroaki Ikeda

  24. Department of Medical Innovation, Osaka University Hospital, Suita, Japan

    Tomomi Yamada

  25. FIVERINGS CO., LTD., Osaka, Japan

    Masaharu Osako, Kaoru Hirai & Hiroshi Miyamoto

Authors
  1. Yasuhiro Nagata
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  2. Shinichi Kageyama
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  3. Takeshi Ishikawa
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  4. Satoshi Kokura
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  5. Tetsuya Okayama
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  6. Tetsuya Abe
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  7. Masahiko Murakami
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  8. Koji Otsuka
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  9. Tomotake Ariyoshi
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  10. Takashi Kojima
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  11. Ken Taniguchi
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  12. Shinichiro Kobayashi
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  13. Hideaki Shimada
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  14. Satoshi Yajima
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  15. Takashi Suzuki
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  18. Toshiaki Shichinohe
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  19. Shugo Ueda
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  20. Kengo Kanetaka
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  21. Akira Yoneda
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  22. Hisashi Wada
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  23. Yuichiro Doki
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  35. Eriko Fukuda
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  36. Kei Yamaguchi
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  37. Eiichi Sato
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  38. Hiroaki Ikeda
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  39. Tomomi Yamada
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  40. Masaharu Osako
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  41. Kaoru Hirai
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  42. Hiroshi Miyamoto
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  43. Takashi Watanabe
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  44. Hiroshi Shiku
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Contributions

YN, SK, TY, and HS contributed to the design of the study. YN, TI, SK, TO, TA, MM, KO, TA, TK, KT, SK, HS, SY, TS, SH, TT, TS, SU, KK, AY, HW, YD, HY, MK, MO, HY, KK, MK, YK, and MK contributed to patient recruitment, treatment, and clinical data collection. YM, NG, EF, and KY contributed to immune reaction data. TS and ES contributed to immunohistochemical staining of tumor tissues. YN, SK, HI, TY, MO, KH, HM, and TW interpreted the data. TY and MO performed the statistical analyses. YN and SK wrote the manuscript. All authors contributed to draft revisions and approved the final manuscript.

Corresponding authors

Correspondence to Shinichi Kageyama or Hiroshi Shiku.

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Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in our studies involving human participants were conducted in accordance with Japanese Ethical Guidelines for Clinical Research, Japanese Guidelines for Medical and Health Research Involving Human Subjects, and the Helsinki Declaration. The Institutional Review Board reviewed and approved the protocol and the informed consent documents and their amendments before use (Mie University approval number F2408005).

Informed consent

Written informed consent to participate in the study and for the use of clinical data for research and publication was obtained from all patients included in the studies: Mie University approval number F2408005.

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Nagata, Y., Kageyama, S., Ishikawa, T. et al. Prognostic significance of NY-ESO-1 antigen and PIGR expression in esophageal tumors of CHP-NY-ESO-1-vaccinated patients as adjuvant therapy. Cancer Immunol Immunother 71, 2743–2755 (2022). https://doi.org/10.1007/s00262-022-03194-5

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