Natural Killer Cell Recruitment and Activation Are Regulated by CD47 Expression in the Tumor Microenvironment.

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  • Additional Information
    • Source:
      Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101614637 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2326-6074 (Electronic) Linking ISSN: 23266066 NLM ISO Abbreviation: Cancer Immunol Res Subsets: MEDLINE
    • Publication Information:
      Original Publication: Philadelphia, PA : American Association for Cancer Research, [2013]-
    • Subject Terms:
      Gene Expression*; CD47 Antigen/*genetics ; Killer Cells, Natural/*immunology ; Killer Cells, Natural/*metabolism ; Tumor Microenvironment/*genetics ; Tumor Microenvironment/*immunology; Animals ; Apoptosis ; CD47 Antigen/metabolism ; Disease Models, Animal ; Energy Metabolism/drug effects ; Humans ; Killer Cells, Natural/drug effects ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Melanoma, Experimental ; Mice ; Mice, Knockout ; Mitochondria/genetics ; Mitochondria/metabolism ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/mortality ; Prognosis ; RNA, Messenger ; Reactive Oxygen Species/metabolism ; Stress, Physiological ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Thrombospondin 1/pharmacology
    • Abstract:
      Elevated CD47 expression in some cancers is associated with decreased survival and limited clearance by phagocytes expressing the CD47 counterreceptor SIRPα. In contrast, elevated CD47 mRNA expression in human melanomas was associated with improved survival. Gene-expression data were analyzed to determine a potential mechanism for this apparent protective function and suggested that high CD47 expression increases recruitment of natural killer (NK) cells into the tumor microenvironment. The CD47 ligand thrombospondin-1 inhibited NK cell proliferation and CD69 expression in vitro Cd47 -/- NK cells correspondingly displayed augmented effector phenotypes, indicating an inhibitory function of CD47 on NK cells. Treating human NK cells with a CD47 antibody that blocks thrombospondin-1 binding abrogated its inhibitory effect on NK cell proliferation. Similarly, treating wild-type mice with a CD47 antibody that blocks thrombospondin-1 binding delayed B16 melanoma growth, associating with increased NK cell recruitment and increased granzyme B and interferon-γ levels in intratumoral NK but not CD8 + T cells. However, B16 melanomas grew faster in Cd47 -/- than in wild-type mice. Melanoma-bearing Cd47 -/- mice exhibited decreased splenic NK cell numbers, with impaired effector protein expression and elevated exhaustion markers. Proapoptotic gene expression in Cd47 -/- NK cells was associated with stress-mediated increases in mitochondrial proton leak, reactive oxygen species, and apoptosis. Global gene-expression profiling in NK cells from tumor-bearing mice identified CD47-dependent transcriptional responses that regulate systemic NK activation and exhaustion. Therefore, CD47 positively and negatively regulates NK cell function, and therapeutic antibodies that block inhibitory CD47 signaling can enhance NK immune surveillance of melanomas.
      (©2019 American Association for Cancer Research.)
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    • Grant Information:
      ZIA SC009172-30 United States ImNIH Intramural NIH HHS
    • Accession Number:
      0 (CD47 Antigen)
      0 (CD47 protein, human)
      0 (RNA, Messenger)
      0 (Reactive Oxygen Species)
      0 (Thrombospondin 1)
    • Publication Date:
      Date Created: 20190801 Date Completed: 20200907 Latest Revision: 20210110
    • Publication Date:
      20240829
    • Accession Number:
      PMC6726576
    • Accession Number:
      10.1158/2326-6066.CIR-18-0367
    • Accession Number:
      31362997