Monoclonal antibodies targeting the immune checkpoint Programmed Death-1 (aPD-1 mAbs) have demonstrated impressive benefits for the treatment of some cancers; yet, these drugs are not always effective and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. Here we employed in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real-time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time-points after administration. However, this engagement is transient, as aPD-1 mAbs are captured within minutes from the T cell surface by PD-1– tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug's Fc domain glycan and on Fcγ- receptors (FcγRs) expressed by host myeloid cells, and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of FcγRs prior to aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield new insight into aPD-1 target engagement in vivo and identify specific Fc : FcγR interactions that can be modulated to improve checkpoint blockade therapy.
Massachusetts General Hospital