PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors Journal Article


Authors: Curran, M. A.; Montalvo, W.; Yagita, H.; Allison, J. P.
Article Title: PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors
Abstract: Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding αPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-γ production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-γ/TNF-α double-producing CD8+ T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumorspecific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
Keywords: controlled study; protein expression; unclassified drug; nonhuman; cd8+ t lymphocyte; cell proliferation; animal cell; mouse; animals; bone marrow cells; melanoma; animal experiment; animal model; regulatory t lymphocyte; tumor necrosis factor alpha; immunotherapy; gamma interferon; cancer vaccines; t-lymphocytes, regulatory; lymph node; melanoma b16; melanoma, experimental; cellular distribution; cytokine production; effector cell; bone marrow cell; microenvironment; interferon-gamma; lymphocytic infiltration; cytotoxic t lymphocyte antigen 4; tumor rejection; vaccine; antigens, differentiation; regulator protein; eragrostis tef; flt3-ligand; pd-l1; programmed death 1; granzymes
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 107
Issue: 9
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2010-03-02
Start Page: 4275
End Page: 4280
Language: English
DOI: 10.1073/pnas.0915174107
PUBMED: 20160101
PROVIDER: scopus
PMCID: PMC2840093
DOI/URL:
Notes: --- - "Cited By (since 1996): 18" - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus"
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  1. James P Allison
    129 Allison
  2. Michael Andrew Curran
    15 Curran