A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy.

ABSTRACT: It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4 ^h/h ) or human CD34⁺ stem cell-reconstituted NSG™ mice. In Ctla4 ^h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody

SUBMITTER: Du X 

PROVIDER: S-EPMC5939050 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature