PRTN3 promotes IL33/Treg-mediated tumor immunosuppression by enhancing the M2 polarization of tumor-associated macrophages in lung adenocarcinoma.

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Tác giả: Chong Chen, Huilin Chen, Tsung-Hsien Chuang, Zhaojun Duan, Jiayu Jiang, Tong Li, Yunping Luo, Lei Ma, Lingyu Ma, Qin Si, Huifang Su, Chen Zhang, Chunxing Zhao

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: Ireland : Cancer letters , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 710547

The immunosuppressive tumor microenvironment (TME) shaped by tumor-associated macrophages (TAMs) is essential for lung adenocarcinoma (LUAD) immune tolerance and tumor progression. Here, we first reported that proteinase 3 (PRTN3) promoted the alternative activation (M2) of TAMs and enhanced IL33/regulatory T cells (Tregs)-mediated tumor immunosuppression in LUAD. Firstly, clinical analysis revealed PRTN3 was highly expressed in TAMs and correlated with the tumor progression and poor prognosis in LUAD patients. Meanwhile, by using the myeloid cells-specific Prtn3-knockout mouse model, we demonstrated Prtn3 deficiency in macrophages remolded the immunosuppressive TME and suppressed tumor growth. The mechanism studies uncovered a novel signaling pathway that PRTN3 up-regulated IL33 expression in TAMs by suppressing AKT-mediated ubiquitinated degradation of FOXO1, which subsequently activated Il33 transcription. Furthermore, lack of PRTN3 or FOXO1 in macrophages greatly restrained IL33-induced Treg differentiation. Importantly, selective knockout of Prtn3 in macrophages significantly enhanced the antitumor effect of anti-PD1 therapy in the mouse model of LUAD. Thus, our work demonstrated that PRTN3 in macrophages, served as a key immunoregulator, contributed to impede the antitumor immune response through reinforcing the TAMs/Tregs crosstalk, which provided valuable insights to improve the immunotherapeutic effect by functional remodeling of TAMs to alleviate immunosuppression in LUAD.
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