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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.

  • Author(s): Somasundaram, Rajasekharan;
  • Connelly, Thomas;
  • Choi, Robin;
  • Choi, Hyeree;
  • Samarkina, Anastasia;
  • Li, Ling;
  • Gregorio, Elizabeth;
  • Chen, Yeqing;
  • Thakur, Rohit;
  • Abdel-Mohsen, Mohamed;
  • Beqiri, Marilda;
  • Kiernan, Meaghan;
  • Perego, Michela;
  • Wang, Fang;
  • Xiao, Min;
  • Brafford, Patricia;
  • Yang, Xue;
  • Xu, Xiaowei;
  • Secreto, Anthony;
  • Danet-Desnoyers, Gwenn;
  • Traum, Daniel;
  • Kaestner, Klaus H;
  • Huang, Alexander C;
  • Hristova, Denitsa;
  • Wang, Joshua;
  • Fukunaga-Kalabis, Mizuho;
  • Krepler, Clemens;
  • Ping-Chen, Fang;
  • Zhou, Xiangyang;
  • Gutierrez, Alexis;
  • Rebecca, Vito W;
  • Vonteddu, Prashanthi;
  • Dotiwala, Farokh;
  • Bala, Shashi;
  • Majumdar, Sonali;
  • Dweep, Harsh;
  • Wickramasinghe, Jayamanna;
  • Kossenkov, Andrew V;
  • Reyes-Arbujas, Jorge;
  • Santiago, Kenisha;
  • Nguyen, Tran;
  • Griss, Johannes;
  • Keeney, Frederick;
  • Hayden, James;
  • Gavin, Brian J;
  • Weiner, David;
  • Montaner, Luis J;
  • Liu, Qin;
  • Peiffer, Lukas;
  • Becker, Jürgen;
  • Burton, Elizabeth M;
  • Davies, Michael A;
  • Tetzlaff, Michael T;
  • Muthumani, Kar;
  • Wargo, Jennifer A;
  • Gabrilovich, Dmitry;
  • Herlyn, Meenhard
  • et al.
Abstract

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

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