Sharma et al. demonstrated that the combination of the innate immune TLR1/2 agonist, Pam3CSK4, with anti-CTLA-4 in the B16F10 mouse melanoma model resulted in enhanced tumor rejection and improved survival with immunological memory. Enhanced efficacy depended on CD8+ and CD4+ T cells and correlated with increased IFNγ and granzyme B expression in intratumoral effector cells, and with increased intratumoral Treg depletion due to higher expression of FcγRIV on macrophages and increased ADCC of anti-CTLA-4-coated Tregs in the tumor. The combination was also effective in a pancreatic tumor model and may have translational value.
Contributed by Katherine Turner
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, Fcgamma receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcgamma 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.