CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer

Maosheng Cheng, Shuang Chen, Kang Li, Ganping Wang, Gan Xiong, Rongsong Ling, Caihua Zhang, Zhihui Zhang, Hui Han, Zhi Chen, Xiaochen Wang, Yu Liang, Guoli Tian, Ruoxing Zhou, Yan Zhu, Jieyi Ma, Jiahong Liu, Shuibin Lin (), Hao Xu (), Demeng Chen (), Yang Li () and Liang Peng ()
Additional contact information
Maosheng Cheng: The First Affiliated Hospital of Sun Yat-sen University
Shuang Chen: The First Affiliated Hospital of Sun Yat-sen University
Kang Li: The First Affiliated Hospital of Sun Yat-sen University
Ganping Wang: Southern Medical University
Gan Xiong: The First Affiliated Hospital of Sun Yat-sen University
Rongsong Ling: Shenzhen University
Caihua Zhang: The First Affiliated Hospital of Sun Yat-sen University
Zhihui Zhang: The First Affiliated Hospital of Sun Yat-sen University
Hui Han: The First Affiliated Hospital of Sun Yat-sen University
Zhi Chen: The First Affiliated Hospital of Sun Yat-sen University
Xiaochen Wang: The First Affiliated Hospital of Sun Yat-sen University
Yu Liang: The First Affiliated Hospital of Sun Yat-sen University
Guoli Tian: Sun Yat-sen University
Ruoxing Zhou: The First Affiliated Hospital of Sun Yat-sen University
Yan Zhu: The First Affiliated Hospital of Sun Yat-sen University
Jieyi Ma: The First Affiliated Hospital of Sun Yat-sen University
Jiahong Liu: the Fifth Medical Center of PLA General Hospital
Shuibin Lin: The First Affiliated Hospital of Sun Yat-sen University
Hao Xu: Sichuan University
Demeng Chen: The First Affiliated Hospital of Sun Yat-sen University
Yang Li: Anhui Medical University
Liang Peng: the Fifth Medical Center of PLA General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.

Date: 2024
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DOI: 10.1038/s41467-024-46735-5

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