Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+ T cell dysfunction and maintain memory phenotype

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Science Immunology  02 Nov 2018:
Vol. 3, Issue 29, eaat7061
DOI: 10.1126/sciimmunol.aat7061

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Tandem immunotherapy achieves synergy

Immune checkpoint inhibitor therapies bolster the antitumor activity of CD8+ T lymphocytes. Wang et al. used single-cell analysis of tumor-infiltrating lymphocytes to probe the mechanisms responsible for their observation that a combination of blocking anti–PD-1 and agonist anti-GITR antibodies enhanced tumor control in mouse cancer models. This combination immunotherapy led to a synergistic increase in tumor antigen–specific memory precursor effector T cells dependent on availability of the CD226 costimulatory pathway. Biochemical studies in liposomes identified CD226 as an additional target of dephosphorylation mediated by the PD-1–SHP2 complex. These results provide a mechanistic rationale for conducting further clinical trials of combined anti-GITR and anti–PD-1 immunotherapy in human cancer.