Blocking both PD-1 and TIGIT restores CD226 signaling to improve antitumor T-cell response.

  • Major Finding: Blocking both PD-1 and TIGIT restores CD226 signaling to improve antitumor T-cell response.

  • Concept: CD226 phosphorylation is reduced through PD-1's intracellular domain or TIGIT's extracellular domain.

  • Impact: The convergence of these antibodies provides a rationale for use of this dual blockade as an anticancer therapy.


Despite the success of immune checkpoint inhibitors (ICI), only a small subset of patients demonstrate a durable response. The focus now is on combination treatments of these ICIs with other therapeutic agents, and a greater understanding of the complexities around immune checkpoint molecules could show which combinations will be most effective. Therefore, Banta and colleagues investigated the mechanisms behind the synergy of anti–PD-(L)1 and anti-TIGIT antibodies as well as their effects on tumor-specific CD8+ T-cell response. The antitumor efficacy of dual inhibition was previously shown to be reduced upon blockade of CD226, which is regulated by TIGIT, which was confirmed in this study with further evaluation revealing that CD226 knockout mice also had impaired CD8+ T-cell function. Additionally, clinical response to the anti–PD-L1 antibody atezolizumab could be determined using CD226 expression, with higher expression being associated with longer progression-free survival. Biochemical investigation into the relationship between these proteins demonstrated that the Y322 residue in the intracellular domain (ICD) of CD226 in activated T cells is phosphorylated, with robust phosphorylation being observed in cells lacking TIGIT and PD-1. More­over, cells expressing either TIGIT or PD-1 exhibited reduced phosphorylation, suggesting that each protein is able to independently regulate CD226. Blocking PD-1 led to partial restoration of pCD226 more efficiently than TIGIT, with further examination indicating that the PD-1/PD-L1 axis reduced phosphorylation in a PVR (the ligand for CD226)-induced manner moderated by the ICD of PD-1. Conversely, the ICD of TIGIT was not required for CD226 phosphorylation; however, the extracellular domain of TIGIT inhibited both PVR ligand interaction with CD226 as well as the homodimerization of CD226. Overall, this study shows PD-1 and TIGIT together can inhibit the costimulation of CD226 through different mechanisms and supports this combination as a potentially promising treatment in patients with non–small cell lung cancer.

Banta KL, Xu X, Chitre AS, Au-Yeung A, Takahashi C, O'Gorman WE, et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity 2022;55:512–26.e9.

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at