TY - JOUR
T1 - The Tn antigen promotes lung tumor growth by fostering immunosuppression and angiogenesis via interaction with Macrophage Galactose-type lectin 2 (MGL2)
AU - da Costa, Valeria
AU - van Vliet, Sandra J.
AU - Carasi, Paula
AU - Frigerio, Sofía
AU - García, Pablo A.
AU - Croci, Diego O.
AU - Festari, María Florencia
AU - Costa, Monique
AU - Landeira, Mercedes
AU - Rodríguez-Zraquia, Santiago A.
AU - Cagnoni, Alejandro J.
AU - Cutine, Anabela M.
AU - Rabinovich, Gabriel A.
AU - Osinaga, Eduardo
AU - Mariño, Karina V.
AU - Freire, Teresa
N1 - Funding Information: This work was supported by grants from Agencia Nacional de Investigación e Innovación ( FCE1-2017-1-136094 , ANII, Uruguay) and Comisión Sectorial de Investigación Científica (CSIC, UdelaR, ID114) granted to TF, CSICIniciación to VdC and, CSIC Grupos-908 I + D granted to EO), and Argentinean Agency for Promotion of Science and Technology ( PICT 2015–0564 ) to KVM. AMC, AJC, GAR and KVM also thank Sales, Bunge & Born and Baron Foundations for support and Ferioli, Ostry and Caraballo families for kind donations. Funding Information: We are particularly grateful to URBE (Facultad de Medicina, UdelaR) for animal housing and caring and to the Cell Biology Unit (Institut Pasteur Montevideo) for cell sorting. AJC, DOC, GAR and KVM are researchers from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. VdC was supported by a doctoral fellowship from ANII and CAP (UdelaR) AMC and PAG were supported by a doctoral fellowship from CONICET. Funding Information: This work was supported by grants from Agencia Nacional de Investigaci?n e Innovaci?n (FCE1-2017-1-136094, ANII, Uruguay) and Comisi?n Sectorial de Investigaci?n Cient?fica (CSIC, UdelaR, ID114) granted to TF, CSICIniciaci?n to VdC and, CSIC Grupos-908 I + D granted to EO), and Argentinean Agency for Promotion of Science and Technology (PICT 2015?0564) to KVM. AMC, AJC, GAR and KVM also thank Sales, Bunge & Born and Baron Foundations for support and Ferioli, Ostry and Caraballo families for kind donations. Publisher Copyright: © 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/10/10
Y1 - 2021/10/10
N2 - Tn is a tumor-associated carbohydrate antigen that constitutes both a diagnostic tool and an immunotherapeutic target. It originates from interruption of the mucin O-glycosylation pathway through defects involving, at least in part, alterations in core-1 synthase activity, which is highly dependent on Cosmc, a folding chaperone. Tn antigen is recognized by the Macrophage Galactose-type Lectin (MGL), a C-type lectin receptor present on dendritic cells and macrophages. Specific interactions between Tn and MGL shape anti-tumoral immune responses by regulating several innate and adaptive immune cell programs. In this work, we generated and characterized a variant of the lung cancer murine cell line LL/2 that expresses Tn by mutation of the Cosmc chaperone gene (Tn+ LL/2). We confirmed Tn expression by lectin glycophenotyping and specific anti-Tn antibodies, verified abrogation of T-synthase activity in these cells, and confirmed its recognition by the murine MGL2 receptor. Interestingly, Tn+ LL/2 cells were more aggressive in vivo, resulting in larger and highly vascularized tumors than those generated from wild type Tn− LL/2 cells. In addition, Tn+ tumors exhibited an increase in CD11c+ F4/80+ cells with high expression of MGL2, together with an augmented expression of IL-10 in infiltrating CD4+ and CD8+ T cells. Importantly, this immunosuppressive microenvironment was dependent on the presence of MGL2+ cells, since depletion of these cells abrogated tumor growth, vascularization and recruitment of IL-10+ T cells. Altogether, our results suggest that expression of Tn in tumor cells and its interaction with MGL2-expressing CD11c+F4/80+ cells promote immunosuppression and angiogenesis, thus favoring tumor progression.
AB - Tn is a tumor-associated carbohydrate antigen that constitutes both a diagnostic tool and an immunotherapeutic target. It originates from interruption of the mucin O-glycosylation pathway through defects involving, at least in part, alterations in core-1 synthase activity, which is highly dependent on Cosmc, a folding chaperone. Tn antigen is recognized by the Macrophage Galactose-type Lectin (MGL), a C-type lectin receptor present on dendritic cells and macrophages. Specific interactions between Tn and MGL shape anti-tumoral immune responses by regulating several innate and adaptive immune cell programs. In this work, we generated and characterized a variant of the lung cancer murine cell line LL/2 that expresses Tn by mutation of the Cosmc chaperone gene (Tn+ LL/2). We confirmed Tn expression by lectin glycophenotyping and specific anti-Tn antibodies, verified abrogation of T-synthase activity in these cells, and confirmed its recognition by the murine MGL2 receptor. Interestingly, Tn+ LL/2 cells were more aggressive in vivo, resulting in larger and highly vascularized tumors than those generated from wild type Tn− LL/2 cells. In addition, Tn+ tumors exhibited an increase in CD11c+ F4/80+ cells with high expression of MGL2, together with an augmented expression of IL-10 in infiltrating CD4+ and CD8+ T cells. Importantly, this immunosuppressive microenvironment was dependent on the presence of MGL2+ cells, since depletion of these cells abrogated tumor growth, vascularization and recruitment of IL-10+ T cells. Altogether, our results suggest that expression of Tn in tumor cells and its interaction with MGL2-expressing CD11c+F4/80+ cells promote immunosuppression and angiogenesis, thus favoring tumor progression.
KW - Angiogenesis
KW - Lung cancer
KW - Macrophage galactose-type lectin
KW - Tn antigen
KW - Treg
UR - http://www.scopus.com/inward/record.url?scp=85109082462&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.canlet.2021.06.012
DO - https://doi.org/10.1016/j.canlet.2021.06.012
M3 - Article
C2 - 34144098
SN - 0304-3835
VL - 518
SP - 72
EP - 81
JO - Cancer Letters
JF - Cancer Letters
ER -