TIGIT/CD155 blockade enhances anti-PD-L1 therapy in head and neck squamous cell carcinoma by targeting myeloid-derived suppressor cells

Objectives: Anti-PD-1/PD-L1 therapy has recently been approved for head and neck squamous cell carcinoma (HNSCC). However, given that large numbers of patients with HNSCC do not respond to PD-1/PD-L1 antibodies, combination strategies for elevating the response rate need to be further investigated. The goal of this study was to explore the possibility of dual-targeting CD155/TIGIT and PD-1/PD-L1 signalling in HNSCC. Materials and methods: Multiplex flow cytometry was performed to determine the co-expression of CD155 and PD-L1 in human HNSCC and transgenic HNSCC mouse models. The combined application of TIGIT mAb and PD-L1 mAb in a mouse model was used to explore the therapeutic effect. Results: CD155 and PD-L1 were highly co-expressed on myeloid-derived suppressor cells (MDSCs) derived from patients with HNSCC and were inversely associated with the percentage of tumour CD3(+) T and effector memory T cells. CD155(+)PD-L1(+) MDSCs in the mouse model were gradually enriched in the tumour microenvironment in the middle and late stages of tumour progression. Anti-PD-L1 treatment alone upregulated the expression of CD155 on MDSCs and while anti-TIGIT treatment upregulated the expression of PD-L1 on MDSCs in mice. The combined blockade of TIGIT/CD155 and PD-1/PD-L1 signalling in mice significantly inhibited tumour growth, enhanced the percentages of effector T cells and cytokine secretion and elicited immune memory effects. Conclusion: Our study indicated that CD155(+)PD-L1(+) MDSCs are enriched in the tumour microenvironment and blocking TIGIT/CD155 can effectively enhance the response rate of HNSCC to PD-L1 mAb therapy, which provides the clinical potential of co-targeting TIGIT/CD155 and PD-1/PD-L1 signalling.

Automated summary

This study found that CD155 and PD-L1 are highly co-expressed on MDSCs in HNSCC patients, and the combined blockade of TIGIT/CD155 and PD-1/PD-L1 signaling significantly inhibited tumor growth in mouse models, enhanced the percentage of effector T cells, and induced immune memory effects.