TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion
Menée à l'aide d'un modèle murin de mélanome, cette étude démontre que l'injection intratumorale d'un ligand du récepteur TLR1/2 augmente l'efficacité des anti-CTLA-4 contre les cellules cancéreuses en favorisant la réduction du nombre de lymphocytes T régulateurs dans le microenvironnement tumoral
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.Immune checkpoint inhibitors such as anti–CTLA-4 antibody are widely accepted therapeutic options for many cancers, but there is still a considerable gap in achieving their full potential. We explored the potential of activating the innate and adaptive immune pathways together to improve tumor reduction and survival outcomes. We treated a mouse model of melanoma with intratumoral injections of Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4 plus i.p. injections of anti–CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone, and its efficacy depended on CD4 T cells, CD8 T cells, Fcγ receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcγ receptor IV expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment and increasing efficacy of anti–CTLA-4 antibody in the combination treatment. This mechanism could be harnessed to modulate the clinical outcome of anti–CTLA-4 antibodies and possibly other antibody-based immunotherapies.