Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 12, 2021
- Source ID
- 10.1038/s41467-020-20600-7
Entities
People
- Alexander C. Huang
- Alexis Gutierrez
- Anastasia Samarkina
- Andrew V Kossenkov
- Anthony Secreto
- Brian J. Gavin
- Clemens Krepler
- Daniel Traum
- David B. Weiner
- Denitsa Hristova
- Dmitry I. Gabrilovich
- Elizabeth Gregorio
- Elizabeth M. Burton
- Fang Ping-chen
- Fang Wang
- Farokh Dotiwala
- Frederick Keeney
- Gwenn Danet-Desnoyers
- Harsh Dweep
- Hyeree Choi
- James Hayden
- Jayamanna Wickramasinghe
- Jennifer Wargo
- Johannes Griss
- Jorge Reyes-arbujas
- Joshua X. Wang
- Jürgen Becker
- Karuppiah Muthumani
- Kenisha Santiago
- Klaus H. Kaestner
- Ling Li
- Luis Montaner
- Lukas Peiffer
- Marilda Beqiri
- Meaghan Kiernan
- Meenhard Herlyn
- Michael A Davies
- Michael T. Tetzlaff
- Michela Perego
- Min Xiao
- Mizuho Fukunaga-kalabis
- Mohamed Abdel-Mohsen
- Patricia Brafford
- Prashanthi Vonteddu
- Qin Liu
- Rajasekharan Somasundaram
- Robin Choi
- Rohit Thakur
- Shashi Bala
- Sonali Majumdar
- Thomas Connelly
- Tran Nguyen
- Vito W. Rebecca
- Xiangyang Zhou
- Xiaowei Xu
- Xue Yang
- Yeqing Chen
Organizations
- Adelson Foundation
- National Institutes of Health
- United States Department of Defense
- United States Department of Health and Human Services