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TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 5/21/2019, Vol. 116 Issue 21, p10453-10462, 10p
- Publication Year :
- 2019
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- TOLL-like receptors
NATURAL immunity
MACROPHAGES
TUMOR microenvironment
T cells
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 116
- Issue :
- 21
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 136627791
- Full Text :
- https://doi.org/10.1073/pnas.1819004116