Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T_reg cells

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Tiragolumab (anti-TIGIT) combined with atezolizumab (anti-PD-L1) showed improved outcomes in the CITYSCAPE trial.
• The precise mechanism of action for this combination therapy remains unclear.

Purpose of the Study:

• To elucidate the mechanism of response for atezolizumab plus tiragolumab combination therapy.
• To investigate the role of intratumoral immune cells and Fcγ receptor (FcγR) engagement in anti-TIGIT therapy.

Main Methods:

• Analysis of baseline intratumoral macrophages and regulatory T cells in patients.
• Serum sample analysis for macrophage activation markers.
• In vivo studies using mouse tumor models with tiragolumab surrogate antibodies.

Main Results:

• High baseline intratumoral macrophages and regulatory T cells correlated with better outcomes in the combination arm.
• Macrophage activation in serum was linked to clinical benefit in patients receiving atezolizumab plus tiragolumab.
• Tiragolumab surrogate antibodies activated tumor-associated macrophages, monocytes, and dendritic cells via FcγR in mouse models.
• This activation promoted a shift in anti-tumor CD8+ T cells towards a memory-like state.

Conclusions:

• TIGIT checkpoint inhibitors can remodel immunosuppressive tumor microenvironments.
• FcγR engagement is a crucial mechanism for anti-TIGIT antibody efficacy.
• The findings suggest FcγR engagement is a key consideration in developing anti-TIGIT therapies.