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Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47.

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Affiliations

  • 1. Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Zhuhai, China.
      Authors
    • Huang C 1, 3
    • Chen S 1
    (2 authors)
  • 2. School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
      Authors
    • Wang X 2
    • Chen S 2
    • Yan P 2
    • Zhang Q 2
    • Hong N 2
    • Jin W 2
    (6 authors)
  • 3. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
      Authors
    • Huang C 1, 3
    • Wang Y 3
    • He W 3
    (3 authors)
  • 4. Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
      Authors
    • Feng Y 4
    • Wang X 4
    • Wang L 4
    • Wang X 4
    • Chen J 4, 9
    (5 authors)
  • 5. GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China.
      Authors
    • Liao J 5
    (1 author)
    • Show all (9)

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Nature Cancer, 10 Jan 2024, 5(3):500-516
https://doi.org/10.1038/s43018-023-00691-z PMID: 38200243 

Abstract 

Immunosuppressive myeloid cells hinder immunotherapeutic efficacy in tumors, but the precise mechanisms remain undefined. Here, by performing single-cell RNA sequencing in colorectal cancer tissues, we found tumor-associated macrophages and granulocytic myeloid-derived suppressor cells increased most compared to their counterparts in normal tissue and displayed the highest immune-inhibitory signatures among all immunocytes. These cells exhibited significantly increased expression of immunoreceptor tyrosine-based inhibitory motif-bearing receptors, including SIRPA. Notably, Sirpa-/- mice were more resistant to tumor progression than wild-type mice. Moreover, Sirpα deficiency reprogramed the tumor microenvironment through expansion of TAM_Ccl8hi and gMDSC_H2-Q10hi subsets showing strong antitumor activity. Sirpa-/- macrophages presented strong phagocytosis and antigen presentation to enhance T cell activation and proliferation. Furthermore, Sirpa-/- macrophages facilitated T cell recruitment via Syk/Btk-dependent Ccl8 secretion. Therefore, Sirpα deficiency enhances innate and adaptive immune activation independent of expression of CD47 and Sirpα blockade could be a promising strategy to improve cancer immunotherapy efficacy.

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Funding 

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National Natural Science Foundation of China (National Science Foundation of China) (4)

Shenzhen Science and Technology Innovation Commission (1)