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Translational Therapeutics

Mapping of truncated O-glycans in cancers of epithelial and non-epithelial origin

British Journal of Cancer volume 125, pages 1239–1250 (2021)Cite this article

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Abstract

Background

Novel immunotherapies targeting cancer-associated truncated O-glycans Tn (GalNAcα-Ser/Thr) and STn (Neu5Acα2–6GalNacα-Ser/Thr) are promising strategies for cancer treatment. However, no comprehensive, antibody-based mapping of truncated O-glycans in tumours exist to guide drug development.

Methods

We used monoclonal antibodies to map the expression of truncated O-glycans in >700 tissue cores representing healthy and tumour tissues originating from breast, colon, lung, pancreas, skin, CNS and mesenchymal tissue. Patient-derived xenografts were used to evaluate Tn expression upon tumour engraftment.

Results

The Tn-antigen was highly expressed in breast (57%, n = 64), colorectal (51%, n = 140) and pancreatic (53%, n = 108) tumours, while STn was mainly observed in colorectal (80%, n = 140) and pancreatic (56%, n = 108) tumours. We observed no truncated O-glycans in mesenchymal tumours (n = 32) and low expression of Tn (5%, n = 87) and STn (1%, n = 75) in CNS tumours. No Tn-antigen was found in normal tissue (n = 124) while STn was occasionally observed in healthy gastrointestinal tissue. Surface expression of Tn-antigen was identified across several cancers. Tn and STn expression decreased with tumour grade, but not with cancer stage. Numerous xenografts maintained Tn expression.

Conclusions

Surface expression of truncated O-glycans is limited to cancers of epithelial origin, making Tn and STn attractive immunological targets in the treatment of human carcinomas.

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Fig. 1: O-glycan biosynthesis and structure.
Fig. 2: Truncated O-glycans are surface exposed in tumours of epithelial origin.
Fig. 3: Truncated O-glycans are rarely surface exposed in healthy tissue.
Fig. 4: Statistical analysis of expression of truncated O-glycans.
Fig. 5: Tn is conserved on the cell surface after xenografting of tumour cells.

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Data availability

All data included in the study are available upon request to the corresponding author.

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Acknowledgements

We thank laboratory technician Karin Uch Hansen for excellent technical assistance. We are also deeply thankful to Professor Jesper Reibel (jrei@sund.ku.dk) for an extraordinary job evaluating the immunohistochemistry of human cancers and healthy tissues.

Funding

This work was supported by the European Commission (GlycoSkin H2020-ERC), The Friis Foundation, The Michelsen Foundation and the Neye Foundation. TBR has received funds from the University of Copenhagen Faculty of Health and Medical Sciences and The Danish Cancer Society. JWP has received funds from The Danish Cancer Society. The founders did not have any role in the acquisition, analysis of or decision to publish the results.

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  1. These authors contributed equally: Troels Boldt Rømer, Mikkel Koed Møller Aasted.

Authors and Affiliations

  1. Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N, Denmark

    Troels Boldt Rømer, Mikkel Koed Møller Aasted, Johannes Wirenfeldt Pedersen, Amalie Dahl Haue & Hans Heugh Wandall

  2. Department of Pathology and Medicine, School of Dentistry, University of Copenhagen, Copenhagen N, Denmark

    Sally Dabelsteen

  3. Go Therapeutics, Cambridge, MA, USA

    Aaron Groen, Julia Schnabel & Edwin Tan

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Contributions

TBR, MKMA, SD and HHW conceived and designed the study. TBR drafted the manuscript with MKMA and HHW. Experiments were performed by MKMA, SD, TBR, AG, JS, ET, JWP and ADH, while SD, TBR, JS, MKMA and HHW analysed the data with assistance from ET and AG. Statistical analysis was conducted by TBR and MKMA. All authors read and approved the manuscript.

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Correspondence to Hans Heugh Wandall.

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Competing interests

HHW owns stocks and is a consultant for and co-founder of EbuMab, ApS. and GO-Therapeutics, Inc. JWP, HHW and MKMA are co-inventors of a novel antibody targeting truncated O-glycans. The remaining authors declare no competing interests. AG, JS and ET are employed by GO-Therapeutics, Inc.

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TMA material was obtained from US Biomax, Inc. The company informs that all human tissues are collected under HIPPA approved protocols, with full information of the donor and with their consent. All standard medical care has been followed, and protection of the donors’ privacy has been ensured.

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Rømer, T.B., Aasted, M.K.M., Dabelsteen, S. et al. Mapping of truncated O-glycans in cancers of epithelial and non-epithelial origin. Br J Cancer 125, 1239–1250 (2021). https://doi.org/10.1038/s41416-021-01530-7

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