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Mannan-targeting chimeric antigen receptor redirected antifungal activity of NK-92 cells against Candida albicans
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Orientador(es)
Resumo(s)
Chimeric antigen receptors (CARs) offer promising prospects for innovative cell-based therapies against invasive fungal infections such as invasive candidiasis. Here, we have developed 4 CARs targeting Candida albicans with distinct single-chain variable fragments (scFvs): scFv3-CAR, scFv5-CAR, scFv12-CAR, and scFvκ3-1-CAR. In T cells, scFv5-CAR induced IL-2 expression in response to C. albicans hyphae, while scFv3-CAR and scFv12-CAR did not mediate cell activation against C. albicans. Notably, scFvκ3-1-CAR mediated the strongest cell activation against C. albicans yeast, hyphae, and other clinically relevant Candida species. scFvκ3-1-CAR-NK-92 cells exhibited elevated IFN-γ and CD107a expression, reducing C. albicans viability. NOD scid gamma (NSG) mice treated with scFvκ3-1-CAR-NK-92 cells had reduced C. albicans burden in the kidneys 24 hours postinfection. We showed that scFvκ3-1-CAR targets C. albicans mannan but no other glycans in glycan microarray screening analyses. These findings reveal the scFvκ3-1-CAR potential as a therapeutic strategy for treating Candida spp. by modifying peripheral blood mononuclear cells.
Descrição
Funding Information: This work was supported by the Funda\u00E7\u00E3o de Amparo \u00E0 Pesquisa do Estado de S\u00E3o Paulo (Grant numbers 2023/06496-0 ; 2022/14669-9 ; 2021/02758-4 ; 2020/16738-2 ; 2019/26074-7 ; 2018/18538-0 ) to TAS and GYC, and National Institute of Science and Technology in Human Pathogenic Fungi (Conselho Nacional de Desenvolvimento Cient\u00EDfico e Tecnol\u00F3gico, CNPq; grant number 405934/2022-0 ) to GHG and TAS. Funding Information: GYC and TAS conceived and designed the experiments, performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft. JGG, MPM, PKMOB, BS, ADM, YL, SJM, and TF performed the experiments, analyzed the data, prepared figures and/or tables, and approved the final draft. DS, PVBP, TFR, and GHG performed the experiments and approved the final draft. ASP (performed the experiments and approved the final draft). All animal experiments were approved by the Committee on Ethics in Animal Research of Ribeir\u00E3o Preto Medical School (protocol 071/2021). C. auris (clinical isolates 467, 468, and 469) were available to make a library of GHG.\u2019s lab, and the Committee of Ethics of the University of S\u00E3o Paulo, Campus of Ribeir\u00E3o Preto, Brazil (Permit Number 08.1.1277.53.6; studies on the interaction of fungal pathogens with animals) approved all protocols to work with clinical isolates. This work was supported by the Funda\u00E7\u00E3o de Amparo \u00E0 Pesquisa do Estado de S\u00E3o Paulo (Grant numbers 2023/06496-0; 2022/14669-9; 2021/02758-4; 2020/16738-2; 2019/26074-7; 2018/18538-0) to TAS and GYC, and National Institute of Science and Technology in Human Pathogenic Fungi (Conselho Nacional de Desenvolvimento Cient\u00EDfico e Tecnol\u00F3gico, CNPq; grant number 405934/2022-0) to GHG and TAS. The glycan microarray studies were performed in the Carbohydrate Microarray Facility at the Glycosciences Laboratory with support from Wellcome Trust Biomedical Resource grants (099197/Z/12/Z, 108430/Z/15/Z, and 218304/Z/19/Z) and in part by the March of Dimes Prematurity research center grant (22-FY18-82). The glycan microarrays contain many saccharides provided by collaborators whom we thank, as well as members of the Glycosciences Laboratory for their contribution in the establishment of the NGL-based microarray system. The funders had no role in study design, data collection and analysis, publication decisions, or manuscript preparation [ 62\u201364]. Funding Information: The glycan microarray studies were performed in the Carbohydrate Microarray Facility at the Glycosciences Laboratory with support from Wellcome Trust Biomedical Resource grants (099197/Z/12/Z, 108430/Z/15/Z, and 218304/Z/19/Z) and in part by the March of Dimes Prematurity research center grant (22-FY18-82). The glycan microarrays contain many saccharides provided by collaborators whom we thank, as well as members of the Glycosciences Laboratory for their contribution in the establishment of the NGL-based microarray system. Publisher Copyright: © 2025 International Society for Cell & Gene Therapy
Palavras-chave
Candida albicans CAR-NK cells CAR-T cells chimeric antigen receptor invasive candidiasis mannan Immunology and Allergy Immunology Oncology Genetics(clinical) Cell Biology Transplantation Cancer Research SDG 3 - Good Health and Well-being