MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma
Abstract Dendritic cells (DC) are key players in antitumor immune responses. Tumors exploit their plasticity to escape immune control; their aberrant surface carbohydrate patterns (e.g., glycans) shape immune responses through lectin binding, and manipulate the metabolism of immune cells, including...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56392-x |
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| author | Camille Niveau Mélanie Cettour-Cave Stéphane Mouret Eleonora Sosa Cuevas Mylene Pezet Benoît Roubinet Hugo Gil Florence De Fraipont Ludovic Landemarre Julie Charles Philippe Saas Caroline Aspord |
| author_facet | Camille Niveau Mélanie Cettour-Cave Stéphane Mouret Eleonora Sosa Cuevas Mylene Pezet Benoît Roubinet Hugo Gil Florence De Fraipont Ludovic Landemarre Julie Charles Philippe Saas Caroline Aspord |
| author_sort | Camille Niveau |
| collection | DOAJ |
| description | Abstract Dendritic cells (DC) are key players in antitumor immune responses. Tumors exploit their plasticity to escape immune control; their aberrant surface carbohydrate patterns (e.g., glycans) shape immune responses through lectin binding, and manipulate the metabolism of immune cells, including DCs to alter their function and escape immune surveillance. DC metabolic reprogramming could induce immune subversion and tumor immune escape. Here we explore metabolic features of human DC subsets (cDC2s, cDC1s, pDCs) in melanoma, at single cell level, using the flow cytometry-based SCENITH (Single-Cell ENergetIc metabolism by profiling Translation inHibition) method. We demonstrate that circulating and tumor-infiltrating DC subsets from melanoma patients are characterized by altered metabolism, which is linked to their activation status and profile of immune checkpoint expression. This altered metabolism influences their function and affects patient clinical outcome. Notably, melanoma tumor cells directly remodel the metabolic profile of DC subsets, in a glycan-dependent manner. Strikingly, modulation of the mTOR/AMPK-dependent metabolic pathways and/or the MCT1 lactate transporter rescue cDC2s and cDC1s from skewing by tumor-derived glycans, Sialyl-Tn antigen and Fucose, and restore anti-tumor T-cell fitness. Our findings thus open the way for appropriate tuning of metabolic pathways to rescue DCs from tumor hijacking and restore potent antitumor responses. |
| format | Article |
| id | doaj-art-b22e701bc7fe44f1a6c1942a4ae53c12 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b22e701bc7fe44f1a6c1942a4ae53c122025-02-02T12:32:14ZengNature PortfolioNature Communications2041-17232025-01-0116112410.1038/s41467-025-56392-xMCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanomaCamille Niveau0Mélanie Cettour-Cave1Stéphane Mouret2Eleonora Sosa Cuevas3Mylene Pezet4Benoît Roubinet5Hugo Gil6Florence De Fraipont7Ludovic Landemarre8Julie Charles9Philippe Saas10Caroline Aspord11Institute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Univ. Grenoble AlpesInstitute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Univ. Grenoble AlpesDermatology, Allergology & Photobiology Department, Univ. Grenoble Alpes, CHU Grenoble AlpesInstitute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Univ. Grenoble AlpesOptical Microscopy and Flow Cytometry (MicroCell), Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR 5309, Univ. Grenoble AlpesGLYcoDiagDepartment of Anatomopathology, Grenoble Alpes University Hospital CenterMedical Unit of Molecular genetic (hereditary diseases and oncology), Grenoble University HospitalGLYcoDiagDermatology, Allergology & Photobiology Department, Univ. Grenoble Alpes, CHU Grenoble AlpesInstitute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Univ. Grenoble AlpesInstitute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Univ. Grenoble AlpesAbstract Dendritic cells (DC) are key players in antitumor immune responses. Tumors exploit their plasticity to escape immune control; their aberrant surface carbohydrate patterns (e.g., glycans) shape immune responses through lectin binding, and manipulate the metabolism of immune cells, including DCs to alter their function and escape immune surveillance. DC metabolic reprogramming could induce immune subversion and tumor immune escape. Here we explore metabolic features of human DC subsets (cDC2s, cDC1s, pDCs) in melanoma, at single cell level, using the flow cytometry-based SCENITH (Single-Cell ENergetIc metabolism by profiling Translation inHibition) method. We demonstrate that circulating and tumor-infiltrating DC subsets from melanoma patients are characterized by altered metabolism, which is linked to their activation status and profile of immune checkpoint expression. This altered metabolism influences their function and affects patient clinical outcome. Notably, melanoma tumor cells directly remodel the metabolic profile of DC subsets, in a glycan-dependent manner. Strikingly, modulation of the mTOR/AMPK-dependent metabolic pathways and/or the MCT1 lactate transporter rescue cDC2s and cDC1s from skewing by tumor-derived glycans, Sialyl-Tn antigen and Fucose, and restore anti-tumor T-cell fitness. Our findings thus open the way for appropriate tuning of metabolic pathways to rescue DCs from tumor hijacking and restore potent antitumor responses.https://doi.org/10.1038/s41467-025-56392-x |
| spellingShingle | Camille Niveau Mélanie Cettour-Cave Stéphane Mouret Eleonora Sosa Cuevas Mylene Pezet Benoît Roubinet Hugo Gil Florence De Fraipont Ludovic Landemarre Julie Charles Philippe Saas Caroline Aspord MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma Nature Communications |
| title | MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma |
| title_full | MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma |
| title_fullStr | MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma |
| title_full_unstemmed | MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma |
| title_short | MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma |
| title_sort | mct1 lactate transporter blockade re invigorates anti tumor immunity through metabolic rewiring of dendritic cells in melanoma |
| url | https://doi.org/10.1038/s41467-025-56392-x |
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