In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy

被引:497
作者
Arlauckas, Sean P. [1 ,2 ,3 ]
Garris, Christopher S. [1 ,4 ]
Kohler, Rainer H. [1 ]
Kitaoka, Maya [5 ]
Cuccarese, Michael F. [1 ]
Yang, Katherine S. [1 ]
Miller, Miles A. [1 ,2 ]
Carlson, Jonathan C. [1 ]
Freeman, Gordon J. [6 ]
Anthony, Robert M. [5 ]
Weissleder, Ralph [1 ,2 ,3 ]
Pittet, Mikael J. [1 ,2 ]
机构
[1] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Dept Radiol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA
[3] Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA
[4] Harvard Med Sch, Grad Program Immunol, Boston, MA 02115 USA
[5] Massachusetts Gen Hosp, Ctr Immunol & Infect Dis, 149 8th St, Charlestown, MA 02129 USA
[6] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
关键词
IMMUNE CHECKPOINT BLOCKADE; PD-1; BLOCKADE; SINGLE-CELL; CANCER; ANTIBODY; MECHANISMS; EXPRESSION; RECEPTORS; MODULATE; OCCURS;
D O I
10.1126/scitranslmed.aal3604
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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-1mAbs in real time and at subcellular resolution in mice. We show that aPD-1mAbs 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 Fc gamma receptors (Fc gamma Rs) expressed by host myeloid cells and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of Fc gamma Rs 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/Fc gamma R interactions that can be modulated to improve checkpoint blockade therapy.
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页数:10
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