Selective SIRP? blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance.

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

SUBMITTER: Gauttier V 

PROVIDER: S-EPMC7598080 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature