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Synergistic effects of CTLA‐4 blockade with tremelimumab and elimination of regulatory T lymphocytes in vitro and in vivo
Author(s) -
Suarez Natalia,
Alfaro Carlos,
Dubrot Juan,
Palazon Asis,
Bolaños Elixabet,
Erro Lorena,
HervasStubbs Sandra,
MartinezForero Ivan,
MoralesKastresana Aizea,
MartinAlgarra Salvador,
Sangro Bruno,
Lecanda Fernando,
PerezGracia Jose L.,
Gonzalez Alvaro,
Melero Ignacio
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25681
Subject(s) - tremelimumab , cd80 , ipilimumab , ctla 4 , cytotoxic t cell , t cell , immunology , il 2 receptor , cancer research , cd86 , in vivo , immunotherapy , medicine , biology , in vitro , immune system , cd40 , biochemistry , microbiology and biotechnology
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‐2Rγ −/− 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.