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

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