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Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-Cell infiltration, proliferation, and cytokine production

Curran, Michael A., Kim, Myoungjoo, Montalvo, Welby, Al-Shamkhani, Aymen and Allison, James P. (2011) Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-Cell infiltration, proliferation, and cytokine production PLoS ONE, 6, (4), e19499-[11pp]. (doi:10.1371/journal.pone.0019499). (PMID:21559358).

Record type: Article

Abstract

BACKGROUND: The 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 FINDINGS: We 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/SIGNIFICANCE: This 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.

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Published date: 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 341581
URI: http://eprints.soton.ac.uk/id/eprint/341581
ISSN: 1932-6203
PURE UUID: 1fc1653a-eb67-4b5c-8dea-a86440a0c01d

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Date deposited: 30 Jul 2012 09:24
Last modified: 18 Jul 2017 05:34

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Contributors

Author: Michael A. Curran
Author: Myoungjoo Kim
Author: Welby Montalvo
Author: James P. Allison

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