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Human CSPG4-targeting CAR-macrophages inhibit melanoma growth
Daniel Greiner1, Qian Xue1, Trinity Qa Waddell1
1Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
Abstract:
Approximately half of melanoma patients relapse or fail to respond to current standards of care, highlighting the need for new treatment options. Engineering T-cells with chimeric antigen receptors (CARs) has revolutionized the treatment of hematological malignancies but has been clinically less effective in solid tumors. We therefore sought to engineer alternative immune cell types to inhibit melanoma progression. Engineering macrophages with CARs has emerged as a promising approach to overcome some of the challenges faced by CAR-T cells; however, whether these engineered macrophages can effectively inhibit melanoma growth is unknown. To determine whether CAR-macrophages (CAR-Ms) specifically target and kill melanoma cells, we engineered CAR-Ms targeting chondroitin sulfate proteoglycan 4 (CSPG4), an antigen expressed in melanoma. CSPG4-targeting CAR-Ms exhibited specific phagocytosis of CSPG4-expressing melanoma cells. We developed 3D approaches to show that CSPG4-targeting CAR-Ms efficiently infiltrated melanoma spheroids. Furthermore, combining CSPG4-targeting CAR-Ms with strategies inhibiting CD47/SIRPα "don't eat me" signaling synergistically enhanced CAR-M-mediated phagocytosis and robustly inhibited melanoma spheroid growth in 3D. Importantly, CSPG4-targeting CAR-Ms inhibited melanoma tumor growth in mouse models. These results suggest engineering macrophages against melanoma antigens is a promising solid tumor immunotherapy approach for treating melanoma.
Insights
Engineered macrophages targeting CSPG4 show promise for melanoma immunotherapy. These CAR-macrophages (CAR-Ms) effectively target and destroy melanoma cells, offering a new avenue for solid tumor treatment.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Melanoma treatment faces challenges with relapse and resistance, necessitating novel therapeutic strategies.
- Chimeric antigen receptor (CAR)-T cell therapy is effective in blood cancers but less so in solid tumors like melanoma.
- Engineered macrophages present a potential alternative for solid tumor immunotherapy.
Purpose of the Study:
- To investigate the efficacy of CAR-engineered macrophages (CAR-Ms) in targeting and inhibiting melanoma progression.
- To determine if CAR-Ms targeting chondroitin sulfate proteoglycan 4 (CSPG4) can specifically eliminate melanoma cells.
Main Methods:
- Engineered CAR-Ms to target CSPG4, a melanoma-specific antigen.
- Utilized 3D melanoma spheroid models to assess CAR-M infiltration and efficacy.
- Investigated the synergistic effects of combining CAR-Ms with CD47/SIRPα "don't eat me" signaling inhibitors.
- Evaluated CAR-M efficacy in preclinical mouse models of melanoma.
Main Results:
- CSPG4-targeting CAR-Ms demonstrated specific phagocytosis of CSPG4-expressing melanoma cells.
- CAR-Ms efficiently infiltrated 3D melanoma spheroids.
- Combined CAR-M therapy with CD47/SIRPα inhibition significantly enhanced phagocytosis and inhibited spheroid growth.
- CSPG4-targeting CAR-Ms successfully inhibited melanoma tumor growth in mouse models.
Conclusions:
- Engineered macrophages targeting melanoma antigens represent a viable immunotherapy approach.
- CAR-Ms targeting CSPG4 show significant potential for treating solid tumors like melanoma.
- Combination strategies may enhance the effectiveness of CAR-M therapy in melanoma.
