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

Authors: Curran, M. A.; Kim, M.; Montalvo, W.; Al Shamkhani, A.; Allison, J. P.
Article Title: Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production
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 αCTLA-4 and α4-1BB 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-γ 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 α4-1BB alone. Conclusions/Significance: This study shows that combining T-cell co-inhibitory blockade with αCTLA-4 and active co-stimulation with α4-1BB 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. © 2011 Curran et al.
Keywords: controlled study; protein expression; unclassified drug; drug potentiation; nonhuman; cd8+ t lymphocyte; lymphocyte proliferation; t lymphocyte; mouse; cytotoxic t lymphocyte antigen 4 antibody; cancer immunotherapy; animal experiment; animal model; gamma interferon; lymph node; cancer immunization; cd4+ t lymphocyte; melanoma b16; cytokine production; lymphocytic infiltration; cytotoxic t lymphocyte antigen 4; tumor rejection; melanoma vaccine; b16 flt3 ligand vaccine; b16 granulocyte macrophage colony stimulating factor vaccine; cd137 ligand; cd137 ligand antibody; cytokine antibody; killer cell lectin like receptor g1
Journal Title: PLoS ONE
Volume: 6
Issue: 4
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2011-04-29
Start Page: e19499
Language: English
DOI: 10.1371/journal.pone.0019499
PROVIDER: scopus
PMCID: PMC3085474
PUBMED: 21559358
Notes: --- - "Export Date: 23 June 2011" - "Art. No.: e19499" - "Source: Scopus"
Citation Impact
MSK Authors
  1. James P Allison
    129 Allison
  2. Michael Andrew Curran
    15 Curran
  3. Myoungjoo Kim
    8 Kim