1. Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.
- Author
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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, and Herlyn, Meenhard
- Subjects
B-Lymphocytes ,T-Lymphocytes ,Lymphocytes ,Tumor-Infiltrating ,Mast Cells ,Animals ,Mice ,Transgenic ,Humans ,Melanoma ,Drug Resistance ,Neoplasm ,Programmed Cell Death 1 Receptor ,Sunitinib ,Immune Checkpoint Inhibitors - 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.
- Published
- 2021