학술논문
Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.
Document Type
article
Author
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
Source
Nature communications. 12(1)
Subject
Language
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.