Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance

J Clin Invest. 2020 Nov 2;130(11):6109-6123. doi: 10.1172/JCI135528.


T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.

Keywords: Cancer immunotherapy; Immunology; Macrophages; T cells; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Immunologic Memory*
  • Immunotherapy*
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology


  • Neoplasm Proteins
  • Ptpns1 protein, mouse
  • Receptors, Immunologic