TY - JOUR
T1 - MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response
AU - Gabba, Adele
AU - Attariya, Riem
AU - Behren, Sandra
AU - Pett, Christian
AU - van der Horst, Joost C
AU - Yurugi, Hajime
AU - Yu, Jin
AU - Urschbach, Moritz
AU - Sabin, Juan
AU - Birrane, Gabriel
AU - Schmitt, Edgar
AU - van Vliet, Sandra J
AU - Besenius, Pol
AU - Westerlind, Ulrika
AU - Murphy, Paul V
N1 - Funding Information: This work was supported by Science Foundation Ireland via grant number 16/IA/4419 to P.V.M., by the Irish Research Council via grant number GOIPG/2016/858 and EMBO short-term fellowship 7323 to A.G.. M.U., A.G., E.S., and P.B. acknowledge financial support from the Deutsche Forschungs-gemeinschaft (DFG) (CRC 1066) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC CoG SUPRAVACC- 819856). U.W. acknowledges support from Kempe foundation (JCK-1819.1 and JCK-1819.2). Funding Information: The authors acknowledge Prof. L.L. Kiessling and V. Lensch, MIT Chemistry, for the discussions and training on flow cytometry, Prof. Horst Kunz for the discussion, and Ozgur Cakici and Prof. Jerome Groopman, at the Beth Israel Deaconess Medical Center, for use of the facilities and ITC training. This work was supported by Science Foundation Ireland via grant number 16/IA/4419 to P.V.M., by the Irish Research Council via grant number GOIPG/2016/858 and EMBO short-term fellowship 7323 to A.G.. M.U., A.G., E.S., and P.B. acknowledge financial support from the Deutsche Forschungs-gemeinschaft (DFG) (CRC 1066) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC CoG SUPRAVACC- 819856). U.W. acknowledges support from Kempe foundation (JCK-1819.1 and JCK-1819.2). Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.
PY - 2023/6/21
Y1 - 2023/6/21
N2 - 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.
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.
KW - Antigens, Tumor-Associated, Carbohydrate/chemistry
KW - Dendritic Cells
KW - Galactose/metabolism
KW - Glycopeptides/chemistry
KW - Humans
KW - Lectins, C-Type/metabolism
KW - Macrophages/metabolism
KW - Mucin-1/chemistry
KW - Vaccines
UR - http://www.scopus.com/inward/record.url?scp=85162847018&partnerID=8YFLogxK
U2 - https://doi.org/10.1021/jacs.2c12843
DO - https://doi.org/10.1021/jacs.2c12843
M3 - Article
C2 - 37279388
SN - 0002-7863
VL - 145
SP - 13027
EP - 13037
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 24
ER -