2. Academic Validation
  3. CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer

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

  • Nat Commun. 2024 Apr 1;15(1):2818. doi: 10.1038/s41467-024-46735-5.
Maosheng Cheng # 1,  Shuang Chen # 1,  Kang Li # 1,  Ganping Wang # 2,  Gan Xiong # 1,  Rongsong Ling 3,  Caihua Zhang 1,  Zhihui Zhang 1,  Hui Han 1,  Zhi Chen 1,  Xiaochen Wang 1,  Yu Liang 1,  Guoli Tian 4,  Ruoxing Zhou 1,  Yan Zhu 1,  Jieyi Ma 1,  Jiahong Liu 5,  Shuibin Lin 6,  Hao Xu 7,  Demeng Chen 8,  Yang Li 9,  Liang Peng 10
Affiliations

Affiliations

  • 1 Department of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
  • 2 Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Institute for Advanced Study, Shenzhen University, Shenzhen, 518057, China.
  • 4 Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
  • 5 Senior Department of Oncology, the Fifth Medical Center of PLA General Hospital, NO.8 the east street, Fengtai District, Beijing, 100071, China.
  • 6 Department of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. linshb6@mail.sysu.edu.cn.
  • 7 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China. hao.xu@scu.edu.cn.
  • 8 Department of Medical Oncology; Institute of Precision Medicine; Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. chendm29@mail.sysu.edu.cn.
  • 9 Department of Genetics, School of Life Sciences, Anhui Medical University, Hefei, 230031, China. liyang@ahmu.edu.cn.
  • 10 Senior Department of Oncology, the Fifth Medical Center of PLA General Hospital, NO.8 the east street, Fengtai District, Beijing, 100071, China. pengliang@301hospital.com.cn.
  • # Contributed equally.
PMID: 38561369 DOI: 10.1038/s41467-024-46735-5
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.

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