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Significance Anti–CTLA-4 mAb is able to augment tumor immunity despite CTLA-4 expression by functionally opposing T cell populations: activated effector T (Teff) cells and FOXP3+ CD4+ Treg cells. Here we show that anti–CTLA-4 mAb engineered to be cytotoxic depleted Treg cells effectively in vitro in humans and in vivo in mice. It expanded antigen-specific CD8+ Teff cells when tumor-antigen stimulation was delayed several days to protect them from killing by the mAb. Anti–CTLA-4 mAb modified to exhibit a lesser or no cell-depleting activity failed to show such effects. This strategy of differentially controlling Treg and Teff cells by cytotoxic anti–CTLA-4 mAb to evoke effective tumor immunity will help in designing cancer immunotherapy targeting other molecules commonly expressed by Treg and Teff cells.

Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti–CTLA-4 antibody