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ANTXR1 (TEM8) overexpression in gastric adenocarcinoma makes the protein a potential target of immunotherapy

  • Masoud Sotoudeh
  • Ramin Shakeri
  • Sanford M. Dawsey
  • Bahareh Sharififard
  • Naser Ahmadbeigi
  • Mahmood NaderiEmail author
Original Article

Abstract

Background

Despite the promise of immunotherapy for gastric adenocarcinoma, choices for the selection of effective antigenic targets are very limited. Previously published data and our own in-house computational analysis have suggested that ANTXR1 is a potential target, simultaneously expressed in malignant tumor cells and the endothelial cells of the tumors. However, the expression pattern of ANTXR1 protein in clinical samples of gastric adenocarcinoma has not been fully evaluated.

Methods

Using immunohistochemistry (IHC), we recorded the percentage of ANTXR1 positive cells separately in tumor cells and endothelial cells in the primary tumor, non-tumor gastric tissue adjacent to the primary tumor, and tumor in metastatic sites of 140 gastric adenocarcinoma patients. We also evaluated the association of ANTXR1 expression with the Lauren histological classification of the primary tumors, the patient’s history of neoadjuvant chemotherapy and/or radiotherapy, and the patient’s overall survival.

Results

ANTXR1 was expressed in a mean of 73.89 ± 30.12% of tumor cells and 13.55 ± 20.53% of endothelial cells in the primary tumors. Intestinal adenocarcinomas had lower ANTXR1 expression in the tumor cells and higher ANTXR1 expression in the endothelial cells of the tumor regions, and a history of neoadjuvant therapy was associated with increased ANTXR1 expression in the endothelial cells of the tumor regions. Finally, above median expression of ANTXR1 in the tumor cells of the tumor regions was associated with significantly lower overall patient survival.

Conclusions

Our findings suggest that ANTXR1 is a promising candidate for preclinical and clinical evaluation for gastric adenocarcinoma immunotherapy.

Keywords

Chimeric antigen receptor T cell Gastric adenocarcinoma ANTXR1 TEM8 Antigenic targets Immunotherapy 

Abbreviations

ANTXR1

ANTXR cell adhesion molecule 1

CAR T cell

Chimeric antigen receptor T cells

ERBB2

Erb-b2 receptor tyrosine kinase 2

KDR

Kinase insert domain receptor

MT

Metastatic tumor

NT

Non-tumor region

PDCD1

Programmed cell death 1

PDX

Patient-derived xenograft

PT

Primary tumor

TMA

Tissue microarray

Notes

Author contribution

MS, NA, and MN designed the study; MS and BS performed the IHC evaluations; RS performed the statistical data analyses; and MN and SMD prepared the manuscript.

Funding

This project was funded by Tehran University of Medical Sciences, Digestive Disease Research Institute grant number 38435-37-02-97.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This study was performed after the approval of Institutional Review Board of Tehran University of Medical Sciences (approval ID: IR.TUMS.DDRI.REC.1397.007).

Informed consent

Informed consent was obtained from all patients at the time of surgery for the use of their paraffin-embedded tissue blocks in research after finalizing their diagnostic procedure.

Supplementary material

262_2019_2392_MOESM1_ESM.pdf (105.8 mb)
Supplementary material 1 (PDF 108337 kb)

References

  1. 1.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 68(6):394–424Google Scholar
  2. 2.
    Maconi G, Manes G, Porro GB (2008) Role of symptoms in diagnosis and outcome of gastric cancer. World J Gastroenterol 14(8):1149–1155CrossRefGoogle Scholar
  3. 3.
    Al-Batran S-E, Lorenzen S (2017) Management of locally advanced gastroesophageal cancer: still a multidisciplinary global challenge? Hematol Oncol Clin 31:441–452CrossRefGoogle Scholar
  4. 4.
    Charalampakis N, Economopoulou P, Kotsantis I, Tolia M, Schizas D, Liakakos T, Elimova E, Ajani JA, Psyrri A (2018) Medical management of gastric cancer: a 2017 update. Cancer Med 7:123–133CrossRefGoogle Scholar
  5. 5.
    Bang Y-J, Van Cutsem E, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697CrossRefGoogle Scholar
  6. 6.
    Fuchs CS, Tomasek J, Yong CJ et al (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31–39CrossRefGoogle Scholar
  7. 7.
    Fuchs CS, Doi T, Jang RW et al (2018) Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 4:e180013-eCrossRefGoogle Scholar
  8. 8.
    National Comprehensive Cancer Network (2018) NCCN clinical practice guidelines in oncology, gastric cancer, (Version 2.2018). https://www.nccn.org/professionals/physician_gls/default.aspx#gastric. Accessed 22 May 2018
  9. 9.
    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168:707–723CrossRefGoogle Scholar
  10. 10.
    Raimondi A, Nichetti F, Peverelli G, Bartolomeo MD, Braud FD, Pietrantonio F (2018) Genomic markers of resistance to targeted treatments in gastric cancer: potential new treatment strategies. Pharmacogenomics 19:1047–1068CrossRefGoogle Scholar
  11. 11.
    Croix BS, Rago C, Velculescu V et al (2000) Genes expressed in human tumor endothelium. Science 289:1197–1202CrossRefGoogle Scholar
  12. 12.
    Nanda A, Carson-Walter EB, Seaman S, Barber TD, Stampfl J, Singh S, Vogelstein B, Kinzler KW, Croix BSJCR (2004) TEM8 interacts with the cleaved C5 domain of collagen α3 (VI). Can Res 64:817–820CrossRefGoogle Scholar
  13. 13.
    Szot C, Saha S, Zhang XM et al (2018) Tumor stroma–targeted antibody-drug conjugate triggers localized anticancer drug release. J Clin Investig 128(7):2927–2943CrossRefGoogle Scholar
  14. 14.
    Byrd TT, Fousek K, Pignata A et al (2018) TEM8/ANTXR1-specific CAR T cells as a targeted therapy for triple-negative breast cancer. Can Res 78:489–500CrossRefGoogle Scholar
  15. 15.
    Sotoudeh M, Shirvani SI, Merat S, Ahmadbeigi N, Naderi M (2018) MSLN (Mesothelin), ANTXR1 (TEM8), and MUC3A are the potent antigenic targets for CAR T cell therapy of gastric adenocarcinoma. J Cell Biochem 120(4):5010–5017CrossRefGoogle Scholar
  16. 16.
    Abcam IHC-PARAFFIN PROTOCOL (IHC-P). https://www.abcam.com/ps/pdf/protocols/ihc_p.pdf. Accessed 13 Nov 2017
  17. 17.
    Klebanoff CA, Rosenberg SA, Restifo NP (2016) Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22(1):26CrossRefGoogle Scholar
  18. 18.
    Chaudhary A, Hilton MB, Seaman S et al (2012) TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types. Cancer Cell 21:212–226CrossRefGoogle Scholar
  19. 19.
    Byrd T, Fousek K, Pignata A et al (2016) TEM8/ANTXR1 specific T cells co-target tumor stem cells and tumor vasculature in triple-negative breast cancer. Cancer Res.  https://doi.org/10.1158/1538-7445.AM2016-2312 Google Scholar
  20. 20.
    Szot C, Saha S, Zhang XM et al (2018) Tumor stroma–targeted antibody-drug conjugate triggers localized anticancer drug release. J Clin Invest 128(7):2927–2943CrossRefGoogle Scholar
  21. 21.
    Gutwein LG, Al-Quran SZ, Fernando S, Fletcher BS, Copeland EM, Grobmyer SR (2011) Tumor endothelial marker 8 expression in triple-negative breast cancer. Anticancer Res 31:3417–3422Google Scholar
  22. 22.
    Carson-Walter EB, Watkins DN, Nanda A, Vogelstein B, Kinzler KW, Croix BS (2001) Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res 61:6649–6655Google Scholar
  23. 23.
    Posey AD Jr, Clausen H, June CHJI (2016) Distinguishing truncated and normal MUC1 glycoform targeting from Tn-MUC1-specific CAR T cells: specificity is the key to safety. Immunity 45(5):947–948CrossRefGoogle Scholar
  24. 24.
    Wilke H, Muro K, Van Cutsem E et al (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15:1224–1235CrossRefGoogle Scholar
  25. 25.
    Verheul HM, Pinedo HMJNRC (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7(6):475CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Digestive Diseases Research Center, Digestive Disease Research InstituteTehran University of Medical SciencesTehranIran
  2. 2.Digestive Oncology Research Center, Digestive Disease Research InstituteTehran University of Medical SciencesTehranIran
  3. 3.Metabolic Epidemiology Branch, Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA
  4. 4.Department of Genetics, Colleague of Science, Kazerun BranchIslamic Azad UniversityKazerunIran
  5. 5.Cell-Based Therapies Research Center, Digestive Disease Research InstituteTehran University of Medical SciencesTehranIran

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