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2018 ; 8
(ä): 30
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Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of
intratumoral regulatory T cells or checkpoint blockade?
#MMPMID29713453
Tang F
; Du X
; Liu M
; Zheng P
; Liu Y
Cell Biosci
2018[]; 8
(ä): 30
PMID29713453
show ga
Antibodies to human CTLA-4 have been shown to induce long-lasting protection
against melanoma. It is assumed that these antibodies cause tumor rejection by
blocking negative signaling from the B7-CTLA-4 interactions to enhance priming of
naïve T cells in the lymphoid organs. Recently, we reported that anti-CTLA-4
antibody Ipilimumab effectively induces tumor rejection in vivo although it
blocks neither B7 transendocytosis by CTLA-4 nor CTLA-4 binding to immobilized or
cell-associated B7. Using genetic model in which the anti-CTLA-4 antibodies are
unable to engage more than 50% of CTLA-4, we demonstrated that saturating binding
of CTLA-4 is not necessary for tumor rejection. Our results argue against
B7-CTLA-4 blockade as the mechanism of action for the clinically effective
Ipilimumab. Moreover, Ipilimumab induces tumor rejection even in the absence of
de novo T cell priming in the lymphoid organs. Thus, our data are inconsistent
with key provisions of the prevailing hypothesis on mechanism of action by
anti-CTLA-4 antibodies. Furthermore, anti-CTLA-4 antibodies effectively induce
depletion of regulatory T (Treg) cells in tumor microenvironment but not in the
peripheral lymphoid organs, which is strictly dependent on Fc receptor on host
cells. Based on these data and other recent publications on the subject, we
propose that anti-human CTLA-4 antibodies induce tumor rejection by selective
depletion of Tregs in the tumors rather than blockade of B7-CTLA-4 interaction in
lymphoid organs.