Combinatory use of peptide-drug conjugate and antibody-mediated stimulation to boost macrophage phenotype reprogramming in vitro
Research in the context of cancer immunotherapies has evolved towards modulating the tumour microenvironment (TME) because of its important immunosuppressive activity. TME is not only composed of cancer cells, as many infiltrating immune cells are present in it. A great part of the immune cells pres...
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| Tipo de recurso: | tesis doctoral |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/418506 |
| Acceso en línea: | http://hdl.handle.net/10261/418506 |
| Access Level: | acceso abierto |
| Palabra clave: | Peptides Pharmacology http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation |
| Sumario: | Research in the context of cancer immunotherapies has evolved towards modulating the tumour microenvironment (TME) because of its important immunosuppressive activity. TME is not only composed of cancer cells, as many infiltrating immune cells are present in it. A great part of the immune cells present are tumour-associated macrophages (TAM), these cells contribute to the immunosuppressive effect in the TME. A recently developed peptide-drug conjugate called MACTIDE-Verteporfin (MACTIDE-V) has shown efficacy in reprogramming TAM towards an anti-tumour phenotype. This phenotype reprogramming has been shown to result in slowed tumour growth and reduced lung metastases in a triple-negative breast cancer murine model. In this study we present here, MACTIDE-V combinations with different monoclonal antibodies (mAb’s). The mAb’s studied have an antagonistic effect on macrophage receptors considered immune checkpoints (SIRPα and VISTA), or an agonistic effect on immunostimulant receptors (CD40). These combinations are studied with the objective to find synergistic effects that further potentiate the phenotype reprogramming MACTIDE-V causes. With this objective, an in vitro TAM model based on murine bone marrow-derived macrophages was be treated with combinatory therapies of MACTIDE-V and each of the antibodies studied (anti-SIRPα, anti- CD40 and anti-VISTA) The effect on macrophage phenotype was assessed by studying the pro-inflammatory cytokine and chemokine secretion (IL-12 and CXCL9). We also measured surface expression of phagocytic receptors SIRPα and MARCO, and phagocytic activity of macrophages towards Escherichia coli and 4T1-GFP+ cells. We found combinatory treatments to induce an increased secretion of IL-12 MACTIDE-V+anti-VISTA, MACTIDE-V+ anti-CD40) and CXCL9 (MACTIDE-V+anti-VISTA, MACTIDE-V+ anti-SIRPα). We also found a reduced surface expression of SIRPα in all combinations and an increased percentage of MARCOhigh cells. We did not find MACTIDE-V combination with mAb’s to increase phagocytosis activity towards Escherichia coli when compared to MACTIDE-V monotherapy. We did not find the phagocytic activity towards 4T1-GFP+ cells to be increased in any of the treatment groups studied. These new in vitro results make MACTIDE-V a promising peptide-drug to study in future in vivo assays in combination with other immunotherapeutic strategies such as those studied here |
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