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

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Canada, and approved April 16, 2019 (received for review November 5, 2018) 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.

Original languageEnglish (US)
Pages (from-to)10453-10462
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number21
DOIs
StatePublished - 2019

Keywords

  • CTLA-4
  • TLR1/2 ligand
  • anti-CTLA-4 antibody
  • melanoma
  • tumor immunotherapy

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Research Animal Support Facility
  • Cytogenetics and Cell Authentication Core

Fingerprint

Dive into the research topics of 'TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion'. Together they form a unique fingerprint.

Cite this