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

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

Publication date: May 10, 2019

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.

Sharma, N., Vacher, J., and Allison, J.P. TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion. 22592. 2019 Proc Natl Acad Sci U S A.

Concepts Keywords
Antibodies
Antibody
Blockade
CD4
CD8
Fc Receptor
Immunotherapies
Ligand
Macrophage
Macrophages
Melanoma
Receptor
Sci
Treg
Tumor

Semantics

Type Source Name
gene UNIPROT CD8A
gene UNIPROT CD4
gene UNIPROT TLR4
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT RASA1
gene UNIPROT RGS6
disease MESH cancers
gene UNIPROT CTLA4
gene UNIPROT TLR1

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