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

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, Fc? receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fc? 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.

SUBMITTER: Sharma N

PROVIDER: S-EPMC6534983 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Sharma Naveen N Vacher Jean J Allison James P JP

Proceedings of the National Academy of Sciences of the United States of America 20190510 21

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 comb ...[more]

PMID: 31076558

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Project description:BackgroundThe co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) attenuates immune responses and prevent autoimmunity, however, tumors exploit this pathway to evade the host T-cell response. The T-cell co-stimulatory receptor 4-1BB is transiently upregulated on T-cells following activation and increases their proliferation and inflammatory cytokine production when engaged. Antibodies which block CTLA-4 or which activate 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma as single agents.Methodology/principal findingsWe find that combining ?CTLA-4 and ?4-1BB antibodies in the context of a Flt3-ligand, but not a GM-CSF, based B16 melanoma vaccine promoted synergistic levels of tumor rejection. 4-1BB activation elicited strong infiltration of CD8+ T-cells into the tumor and drove the proliferation of these cells, while CTLA-4 blockade did the same for CD4+ effector T-cells. Anti-4-1BB also depressed regulatory T-cell infiltration of tumors. 4-1BB activation strongly stimulated inflammatory cytokine production in the vaccine and tumor draining lymph nodes and in the tumor itself. The addition of CTLA-4 blockade further increased IFN-? production from CD4+ effector T-cells in the vaccine draining node and the tumor. Anti 4-1BB treatment, with or without CTLA-4 blockade, induced approximately 75% of CD8+ and 45% of CD4+ effector T-cells in the tumor to express the killer cell lectin-like receptor G1 (KLRG1). Tumors treated with combination antibody therapy showed 1.7-fold greater infiltration by these KLRG1+CD4+ effector T-cells than did those treated with ?4-1BB alone.Conclusions/significanceThis study shows that combining T-cell co-inhibitory blockade with ?CTLA-4 and active co-stimulation with ?4-1BB promotes rejection of B16 melanoma in the context of a suitable vaccine. In addition, we identify KLRG1 as a useful marker for monitoring the anti-tumor immune response elicited by this therapy. These findings should aid in the design of future trials for the immunotherapy of melanoma.

Dataset Information

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

Publications

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

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