期刊
INTERNATIONAL JOURNAL OF CANCER
卷 129, 期 2, 页码 374-386出版社
WILEY-BLACKWELL
DOI: 10.1002/ijc.25681
关键词
CTLA-4; T cell; regulatory T cells; dendritic cell; tremelimumab
类别
资金
- MEC/MICINN [SAF2005-03131, SAF2008-03294]
- Redes tematicas de investigacion cooperativa RETIC [RD06/0020/0065]
- Fondo de investigacion sanitaria [FIS PI060932]
- Departamento de Educacion del Gobierno de Navarra
- Departamento de Salud del Gobierno de Navarra (Beca Ortiz de Landazuri)
- European Commission
- Immunonet SUDOE
- Fundacion Mutua Madrilena
- UTE
- Fundacion Cientifica de la Asociacion Espanola Conta el Cancer (AECC)
- DIGNA-BIOTECH
- Pfizer inc.
Anti-CTLA-4 monoclonal antibodies (mAb) that block the interaction of CTLA-4 with CD80 and CD86 such as tremelimumab and ipilimumab are currently being tested in the clinic for cancer treatment exploiting their properties to de-repress tumor-specific cellular immunity. Addition of the fully human anti-CTLA-4 (tremelimumab) to cultures of human T cells with allogenic dendritic cells (DCs) did not increase proliferation. Magnetic bead-mediated elimination of CD4(+) CD25(+) regulatory T cells (T(reg)) before setting up those alloreactive cultures also largely failed to increase primary proliferation. In contrast, predepletion of CD4(+) CD25(+) T(reg) and culture in the presence of tremelimumab synergistically resulted in increased proliferation and DC: T-cell aggregation. These effects were much more prominent in CD4 than in CD8 T cells. The synergy mechanism can be traced to enhanced CTLA-4 expression in effector cells as a result of T(reg) elimination, thereby offering more targets to the blocking antibody. Human T cells and allogenic DCs (derived both from healthy donors and advanced cancer patients) were coinjected in the peritoneum of Rag2(-/-) IL-2R gamma(-/-) mice. In these conditions, tremelimumab injected intravenously did not significantly enhance alloreactive proliferation unless T(reg) cells had been predepleted. Synergistic effects in vivo were again largely restricted to the CD4 T-cell compartment. In addition, T(reg) depletion and CTLA-4 blockade synergistically enhanced specific cytotoxicity raised in culture against autologous EBV-transformed cell lines. Taken together, these experiments indicate that tremelimumab therapy may benefit from previous or concomitant T(reg) depletion.
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