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Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity
Alfonso R Sánchez-Paulete1,2,3, Jaime Mateus-Tique1,2,3, Gurkan Mollaoglu1,2,3
1Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Abstract:
Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T-produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.
Insights
Chimeric antigen receptor (CAR) T-cells targeting tumor-associated macrophages (TAMs) effectively depleted macrophages and slowed tumor growth in mouse models. This novel approach enhanced anti-tumor immunity and survival, offering a promising cancer therapy strategy.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Tumor-associated macrophages (TAMs) are abundant in solid tumors and often promote tumor growth.
- Previous macrophage-depleting strategies for cancer therapy have shown limited clinical success.
Purpose of the Study:
- To develop and evaluate chimeric antigen receptor (CAR) T-cells targeting F4/80 (F4.CAR-T) for TAM depletion in mouse solid tumor models.
- To assess the efficacy and safety of F4.CAR-T cells in enhancing anti-tumor immunity.
Main Methods:
- Development of F4.CAR-T cells targeting the macrophage marker F4/80.
- In vitro and in vivo testing of F4.CAR-T cells in mouse solid tumor models (lung, ovarian, pancreatic).
- Evaluation of tumor growth, mouse survival, and immune responses, including IFNγ production and CD8 T cell expansion.
Main Results:
- F4.CAR-T cells effectively depleted macrophages in vitro and in vivo without observed toxicity.
- F4.CAR-T cell injection delayed tumor growth and significantly extended survival in mice with orthotopic lung tumors.
- Antitumor effects were mediated by F4.CAR-T-produced IFNγ, leading to MHC upregulation and expansion of endogenous CD8 T cells, suggesting immune editing.
Conclusions:
- CAR T-cell targeting of TAMs represents a viable strategy for depleting these protumor cells.
- F4.CAR-T cells demonstrate potential as a novel cancer immunotherapy by enhancing anti-tumor immunity and improving survival outcomes.
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