期刊
CELL RESEARCH
卷 25, 期 2, 页码 208-224出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2015.3
关键词
ipilimumab; CTLA-4 blockade; IL-2; CD122; sCD25; tumor immunotherapy; cancer
类别
资金
- ARC
- Ligue Nationale contre le Cancer (Equipes labellisees)
- SIRIC Socrates
- Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence)
- European Commission (Art-Force)
- European Research Council Advanced Investigator Grant
- Fondation pour la Recherche Medicale (FRM)
- Institut National du Cancer (INCa)
- Fondation de France
- Canceropole Ile-de-France
- Fondation Bettencourt-Schueller
- LabEx Immuno-Oncology
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- National Health and Medical Research Council (NH&MRC) Australia Fellowship
- Victorian Cancer Agency
- NH&MRC Career Development Fellowship
- Associazione Italiana per la Ricerca sul Cancro
- NCI NIH HHS [P30 CA008748] Funding Source: Medline
The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the alpha and beta subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor alpha (IL-2R alpha, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据