期刊
CANCER IMMUNOLOGY RESEARCH
卷 3, 期 3, 页码 236-244出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-14-0226
关键词
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资金
- Swiss National Science Foundation
- Sassella Foundation
- Wilhelm-Sander Foundation
- Cancer League Basel
- FAG Basel
CD40 stimulation on antigen-presenting cells (APC) allows direct activation of CD8(+) cytotoxic T cells, independent of CD4(+) T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial antitumor T-cell responses in mouse models of cancer and early clinical trials. We report here that anti-CD40 treatment induces programmed death ligand-1 (PD-L1) upregulation on tumor-infiltrating monocytes and macrophages, which was strictly dependent on T cells and IFN gamma. PD-L1 expression could be counteracted by coadministration of antibodies blocking the PD-1 (programmed death-1)/PD-L1 axis as shown for T cells from tumor models and human donors. The combined treatment was highly synergistic and induced complete tumor rejection in about 50% of mice bearing MC-38 colon and EMT-6 breast tumors. Mechanistically, this was reflected by a strong increase of IFN gamma and granzyme-B production in intratumoral CD8(+) T cells. Concomitant CTLA-4 blockade further improved rejection of established tumors in mice. This study uncovers a novel mechanism of acquired resistance upon agonistic CD40 stimulation and proposes that the concomitant blockade of the PD-1/PD-L1 axis is a viable therapeutic strategy to optimize clinical outcomes. (C) 2015 AACR.
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