What question did this study set out to answer?

To determine how PD-1 and TIGIT coinhibitory receptors coordinate to suppress anti-tumor CD8+ T cell responses and evaluate the biochemical basis for dual checkpoint inhibition.

March 1, 2022ImmunityOpen Access

Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses

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Authors

KBKarl L. BantaAcentech (United States)XXXiaozheng XuUniversity of California, San Diego ACAvantika S. ChitreSan Francisco General Hospital

Discussion

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Implication

Translational study demonstrates convergent CD226 suppression by PD-1 and TIGIT in cancer, highlighting the rationale for dual checkpoint blockade.

Key Points

To determine how PD-1 and TIGIT coinhibitory receptors coordinate to suppress anti-tumor CD8+ T cell responses and evaluate the biochemical basis for dual checkpoint inhibition.
Assessed anti-tumor responses to PD-1 and TIGIT blockade in preclinical mouse tumor models in the presence or absence of CD226.
Profiled tumor-infiltrating CD8+ T cells and evaluated clinical response in patients with non-small cell lung cancer treated with atezolizumab.
Characterized receptor signaling cascades, specifically examining intracellular domain phosphorylation and competitive binding with the ligand PVR (CD155).
Loss of CD226 reduced the therapeutic efficacy of PD-1 or TIGIT inhibition in preclinical models, while high CD226 expression correlated with improved clinical benefit in atezolizumab-treated lung cancer patients.
PD-1 suppressed phosphorylation of both CD226 and CD28 intracellularly via its ITIM-containing domain, whereas TIGIT impaired CD226 externally by sequestering their shared ligand PVR (CD155).
Simultaneous co-blockade of both TIGIT and PD-1 was required to fully restore CD226 costimulatory signaling and maximize anti-tumor CD8+ T cell activity.

Cite This Study

Banta et al. (2022) studied this question.

synapsesocial.com/papers/6a7d8f601693de70af99a065 https://doi.org/10.1016/j.immuni.2022.02.005

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Implication

Translational study demonstrates convergent CD226 suppression by PD-1 and TIGIT in cancer, highlighting the rationale for dual checkpoint blockade.

Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses

Discussion

Member takes

Implication

Key Points

Cite This Study

Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses

Discussion

Member takes

Implication

Key Points

Cite This Study

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