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

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development. The CT26 mouse colon carcinoma cell line was obtained from American Type Culture Collection. A total of 100,000 CT26 cells was inoculated subcutaneously into the right unilateral flank of the syngeneic BALB/c mice. All mice used were 6-8 week old and female. After approximately 10–12 days, mice bearing tumours of 150–200 mm3 were randomized into treatment groups on the basis of tumour size and treated with anti-mouse PD-L1 (6E11, isotype IgG2a LALAPG, 10 mg per kg), anti-mouse TIGIT (10A7, isotypes IgG2a, mIgG2b, and IgG2a LALAPG, 10 mg per kg), anti-mouse CSF-1R (Bioexcell, BP0213, 30 mg per kg) and/or anti-gp120 control antibodies (IgG2a isotype, to total 35 mg per kg overall antibody dosing). Antibodies were administered once intravenously, and 72 h after treatment, mice were euthanized by asphyxiation and CD45+ cells were collected for scRNA-seq analysis.