PMID- 37279388 OWN - NLM STAT- MEDLINE DCOM- 20230622 LR - 20230701 IS - 1520-5126 (Electronic) IS - 0002-7863 (Print) IS - 0002-7863 (Linking) VI - 145 IP - 24 DP - 2023 Jun 21 TI - MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response. PG - 13027-13037 LID - 10.1021/jacs.2c12843 [doi] AB - Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumor-associated MUC1 glycopeptide antigens has a synergistic impact on antibody production. FAU - Gabba, Adele AU - Gabba A AUID- ORCID: 0000-0001-8240-6482 AD - School of Biological and Chemical Sciences, University of Galway, University Rd., H91 TK33 Galway, Ireland. AD - Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany. FAU - Attariya, Riem AU - Attariya R AD - Institute of Immunology, University Medical Center Mainz, Langenbeckstr.1, 55131 Mainz, Germany. FAU - Behren, Sandra AU - Behren S AD - Department of Chemistry, Umea University, KBC-Building, Linneaus vag 6, S-907 36 Umea, Sweden. FAU - Pett, Christian AU - Pett C AD - Department of Chemistry, Umea University, KBC-Building, Linneaus vag 6, S-907 36 Umea, Sweden. FAU - van der Horst, Joost C AU - van der Horst JC AD - Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. AD - Amsterdam Institute for Infection and Immunity, Cancer Immunology1105 AZ Amsterdam, the Netherlands. FAU - Yurugi, Hajime AU - Yurugi H AD - Institute of Immunology, University Medical Center Mainz, Langenbeckstr.1, 55131 Mainz, Germany. FAU - Yu, Jin AU - Yu J AD - Glycosciences Laboratory, Imperial College London, W12 0NN London, U.K. FAU - Urschbach, Moritz AU - Urschbach M AD - Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany. FAU - Sabin, Juan AU - Sabin J AD - AFFINImeter Scientific & Development Team, Software 4 Science Developments, 15782 Santiago de Compostela, A Coruna, Spain. AD - Departamento de Fisica Aplicada, Facultad de Fisica, Universidad de Santiago de Compostela, 15705 Santiago de Compostela, Spain. FAU - Birrane, Gabriel AU - Birrane G AUID- ORCID: 0000-0002-1759-5499 AD - Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, United States. FAU - Schmitt, Edgar AU - Schmitt E AD - Institute of Immunology, University Medical Center Mainz, Langenbeckstr.1, 55131 Mainz, Germany. FAU - van Vliet, Sandra J AU - van Vliet SJ AD - Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. AD - Amsterdam Institute for Infection and Immunity, Cancer Immunology1105 AZ Amsterdam, the Netherlands. FAU - Besenius, Pol AU - Besenius P AUID- ORCID: 0000-0001-7478-4459 AD - Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany. FAU - Westerlind, Ulrika AU - Westerlind U AD - Department of Chemistry, Umea University, KBC-Building, Linneaus vag 6, S-907 36 Umea, Sweden. FAU - Murphy, Paul V AU - Murphy PV AUID- ORCID: 0000-0002-1529-6540 AD - School of Biological and Chemical Sciences, University of Galway, University Rd., H91 TK33 Galway, Ireland. AD - SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals, University of Galway, University Rd., H91 TK33 Galway, Ireland. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230606 PL - United States TA - J Am Chem Soc JT - Journal of the American Chemical Society JID - 7503056 RN - 0 (Mucin-1) RN - X2RN3Q8DNE (Galactose) RN - 0 (Glycopeptides) RN - 0 (Antigens, Tumor-Associated, Carbohydrate) RN - 0 (Lectins, C-Type) RN - 0 (Vaccines) RN - 0 (MUC1 protein, human) SB - IM MH - Humans MH - *Mucin-1/chemistry MH - Galactose/metabolism MH - Glycopeptides/chemistry MH - Antigens, Tumor-Associated, Carbohydrate/chemistry MH - Lectins, C-Type/metabolism MH - *Vaccines MH - Dendritic Cells MH - Macrophages/metabolism PMC - PMC10288512 COIS- The authors declare no competing financial interest. EDAT- 2023/06/06 19:12 MHDA- 2023/06/22 06:42 PMCR- 2023/06/23 CRDT- 2023/06/06 15:33 PHST- 2023/06/22 06:42 [medline] PHST- 2023/06/06 19:12 [pubmed] PHST- 2023/06/06 15:33 [entrez] PHST- 2023/06/23 00:00 [pmc-release] AID - 10.1021/jacs.2c12843 [doi] PST - ppublish SO - J Am Chem Soc. 2023 Jun 21;145(24):13027-13037. doi: 10.1021/jacs.2c12843. Epub 2023 Jun 6.