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SynNotch-iNOS CAR-Macrophages Remodel the Tumor Immune Microenvironment and Exhibit Antitumor Efficacy via a CD4+ T Cell-Dependent Mechanism

ABSTRACT: Background: Chimeric antigen receptor T-cell (CAR-T) therapy shows limited efficacy against solid tumors due to the immunosuppressive tumor microenvironment (TIME). Macrophages possess superior infiltration capabilities, yet their therapeutic potential remains under-realized. Methods: We engineered a synNotch-iNOS CAR-macrophage (CAR iNOS-M) that releases nitric oxide (NO) upon CD19 recognition. Its efficacy was evaluated in syngeneic, immunocompetent murine models of metastatic melanoma. Results: CAR iNOS-M therapy effectively reprogrammed the pulmonary TIME, inducing potent antitumor responses independent of CD8+ T cells but strictly dependent on CD4+ T cells. Mechanistically, CAR iNOS-M treatment led to a significant reduction in pro-tumorigenic lung interstitial macrophages (IMs), subsequently decreasing platelet factor 4 (PF4) levels. This disruption of the PF4 signaling axis inhibited the polarization of immunosuppressive Th1-Tregs, alleviating T-cell exhaustion. Conclusions: This study delineates a novel indirect mechanism for CAR-M, shifting the focus from direct phagocytosis to strategic TIME remodeling, providing a foundation for treating solid tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE318757 | GEO | 2026/02/27

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.

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 second mathematical model, derived from equations 3 to 6, used in the paper. Reproduction of Figure 5b was achieved by setting alpha_1 = 0.183, in substitution for alpha_1 = 0.2 as quoted in the article. 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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SynNotch-iNOS CAR-Macrophages Remodel the Tumor Immune Microenvironment and Exhibit Antitumor Efficacy via a CD4+ T Cell-Dependent Mechanism

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