Interest
Cancer
Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+ T cell dysfunction and maintain memory phenotypeImmune 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. Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+ T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor–related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+ T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit. Combination therapy decreased CD8+ T cell dysfunction and induced a highly proliferative precursor effector memory T cell phenotype in a CD226-dependent manner. PD-1 inhibition rescued CD226 activity by preventing PD-1–Src homology region 2 (SHP2) dephosphophorylation of the CD226 intracellular domain, whereas GITR agonism decreased TIGIT expression. Unmasking the molecular pathways driving durable antitumor responses will be essential to the development of rational approaches to optimizing cancer immunotherapy.