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 M. Hristova, Joshua X. 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 B. Nguyen, Johannes Griss, Frederick Keeney, James E. Hayden, Brian Gavin, David B. Weiner, Luis J. Montaner, Qin Liu, Lukas Peiffer, Jürgen C. Becker, Elizabeth M. Burton, Michael A. Davies, Michael T. Tetzlaff, Kar Muthumani, Jennifer A. Wargo, Dmitry I. Gabrilovich, Meenhard Herlyn
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 IL2Rγ null (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.