Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy
In: Nature Communications, Jg. 12 (2021), Heft 1
academicJournal
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Zugriff:
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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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Nature Communications, Jg. 12 (2021), Heft 1 |
Veröffentlichung: | eScholarship, University of California, 2021 |
Medientyp: | academicJournal |
Umfang: | 346 |
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