ScholarWorks@성균관대학교

초록

Chimeric antigen receptor macrophages (CAR-M) are emerging as a next-generation cellular modality for therapies ranging from viral infection to solid tumors, leveraging innate phagocytic and antigen-presenting functions. Here, we compared CAR constructs incorporating intracellular signaling domains (ICDs) derived from CD3ζ, Fc gamma receptor IIa (CD32a), complement receptor 3 (CR3), and Toll-like receptor 4 (TLR4) in THP-1-derived monocytes and macrophages. Using an anti-viral SARS-CoV-2 model as a screening platform, we subsequently validated key findings in an anti-tumor mesothelin (MSLN) model. Results indicated that CARCD32a exhibited superior phagocytic capacity compared with CARCD3ζ in both monocytes and macrophages. While combining CR3 (CD11b and CD18) and CD32a domains did not enhance phagocytosis, it significantly increased the expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α). The incorporation of TLR4 signaling domain reduced surface CAR expression and phagocytic capacity but markedly increased inflammatory cytokine induction, suggesting that TLR4-driven cytokine production can be enhanced despite diminished phagocytosis in this setting. Furthermore, following phagocytosis, CAR-monocytes induced antigen-specific CD8+ T cell activation via antigen presentation. Collectively, these findings highlight CD32a-based and combinatorial ICD designs as a framework for functionally tuned CAR-M platform for solid tumor immunotherapy and anti-viral applications.

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