BTN2A1 targeting reprograms M2-like macrophages and TAMs via SYK and MAPK signaling

被引:4
作者
Kerneur, Clement [1 ,2 ]
Foucher, Etienne [1 ]
Casas, Jaime Guillen [1 ]
Colazet, Magali [1 ]
Le, Kieu-Suong [1 ]
Fullana, Marie [1 ]
Bergot, Elise [1 ]
Audemard, Corentin [1 ]
Drapeau, Marion [1 ]
Louche, Pauline [1 ]
Gorvel, Laurent [2 ]
Rouviere, Marie-Sarah [2 ]
Boucherit, Nicolas [2 ]
Audebert, Stephane [3 ]
Magrini, Elena [4 ]
Carnevale, Silvia [4 ]
de Gassart, Aude [1 ]
Madakamutil, Loui [1 ]
Mantovani, Alberto [4 ,5 ,6 ]
Garlanda, Cecilia [4 ]
Agaugue, Sophie [1 ]
Cano, Carla E. [1 ]
Olive, Daniel [2 ]
机构
[1] ImCheck Therapeut, R&D Dept, F-13009 Marseille, France
[2] INSERM, Ctr Rech Cancerol Marseille CRCM, U1068, F-13009 Marseille, France
[3] Aix Marseille Univ, INSERM, CNRS, Inst Paoli Calmettes,Marseille Proteomique, Marseille, France
[4] IRCCS, Humanitas Res Hosp, I-20089 Rozzano, Italy
[5] Humanitas Univ, Dept Biomed Sci, I-20090 Milan, Italy
[6] Queen Mary Univ, William Harvey Res Inst, London EC1M 6BQ, England
来源
CELL REPORTS | 2024年 / 43卷 / 10期
关键词
TUMOR-ASSOCIATED MACROPHAGES; PANCREATIC-CANCER; ACTIVATION; PROGRESSION; TNF; POLARIZATION; PROTEIN; PHOSPHORYLATION; RESISTANCE; INHIBITION;
D O I
10.1016/j.celrep.2024.114773
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAbs), and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift toward an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T cell proliferation and interferon-gamma (IFN gamma) secretion. Mechanistically, BTN2A1 engagement induced spleen tyrosine kinase (SYK) recruitment, leading to sequential SYK and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of SYK or ERK phosphorylation abolished M2 reprogramming upon BTN2A1 engagement. Our findings, derived from an analysis of macrophages from healthy donors and human tumors, underscore the pivotal role of BTN2A1 in immunosuppressive macrophage differentiation and function, offering potential applications in cancer
引用
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页数:31
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