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Characterization of human CD34+ HSPC-derived neutrophils with limited myeloid-derived immunosuppressive cell activity

ABSTRACT: Neutrophils have limited utility as a fundamental research model and transfusion product due to their short lifespan. Here, we cultured CD34+ hematopoietic stem and progenitor cell (HSPC)-derived neutrophils and compared them to peripheral blood neutrophils in terms of morphology, phenotype, and function. Our culture system resulted in morphologically mature CD15+CD11b+CD16high neutrophils with effector functions almost indistinguishable from blood neutrophils, confirmed by a high similarity in transcription and protein abundance patterns. While exhibiting microbial killing capacity and antibody-dependent cellular cytotoxicity, these cells were deficient in myeloid-derived suppressor cell activity. This deficiency in immunosuppressive activity correlated with a distinct granular composition in comparison to blood neutrophils, instead of immunosuppressive characteristics that are currently held to define neutrophil-MDSC phenotype. Taken together, our cultured neutrophils closely resemble blood neutrophils, offering a repository for fundamental research and a step toward an effective transfusion product with limited immunosuppressive activity as a functional property.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300707 | GEO | 2025/08/09

REPOSITORIES: GEO

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Project description:This model of the use of chimeric antigen receptor (CAR)-T cell therapy in the treatment of solid tumours is described in the article: "Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept" Odelaisy León-Triana, Antonio Pérez-Martínez, Manuel Ramírez-Orellana and Víctor M. Pérez-García Cancers 2021, 13, 703.; doi: 10.3390/cancers13040703 Comment: This is the first mathematical model, derived from equations 1 and 2, used in the paper. Reproduction of Fig. 5a was achieved by setting alpha_1 = 0.04, different to the value quoted in the article caption for Fig. 5. Abstract: Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.

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Characterization of human CD34+ HSPC-derived neutrophils with limited myeloid-derived immunosuppressive cell activity

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