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

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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20600-7

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