Journal Article
. 2019 May; 116(21):10453-10462.
doi: 10.1073/pnas.1819004116.

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

Naveen Sharma 1 Jean Vacher 2 James P Allison 1 
Affiliations
  • PMID: 31076558
  •     53 References
  •     20 citations

Abstract

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.

Keywords: CTLA-4; TLR1/2 ligand; anti–CTLA-4 antibody; melanoma; tumor immunotherapy.

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