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Tug-of-war with anti–PD-1
Antibodies against immune checkpoints such as programmed death–1 (PD-1) are gaining increasing prominence in cancer treatment, but even these promising therapeutics do not always work. To be effective in preventing T cells from becoming exhausted, anti–PD-1 antibodies must be able to remain bound to the T cells. Unfortunately, this does not always happen, as Arlauckas et al. discovered. Although anti–PD-1 antibodies initially bound to T cells as intended, the authors found that tumor-associated macrophages quickly removed these antibodies from T cells, thus inactivating them. The researchers also identified a potential way to overcome this problem, showing that inhibition of Fcγ receptors prevented removal of anti–PD-1 and prolonged its effects in vivo.
Monoclonal antibodies (mAbs) targeting the immune checkpoint anti–programmed cell death protein 1 (aPD-1) have demonstrated impressive benefits for the treatment of some cancers; however, these drugs are not always effective, and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. We used 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, and 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 before 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 insight into aPD-1 target engagement in vivo and identify specific Fc/FcγR interactions that can be modulated to improve checkpoint blockade therapy.
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