TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion

Significance To overcome the challenge of nonresponsiveness or low effectiveness to current checkpoint blockade drugs, various combination therapies are under investigation for cancer treatment. In this study, we investigated a combination of Toll-like receptor 1/2 (TLR1/2) ligand and anti–CTLA-4 antibody in a mouse model of melanoma. TLR1/2 ligand enhanced the antitumor efficacy of anti–CTLA-4 by increasing Fcγ receptor IV expression, which in turn increased the depletion of tumor-infiltrating regulatory T cells. Whether ipilimumab causes Treg depletion in human patients is debatable; therefore, combining ipilimumab with Pam3CSK4 could lead to greater antitumor efficacy by introducing this modality. These findings are likely extensible to other checkpoint antibodies in cancer patients.