Jun Li1, Gang Peng1, Kuikui Zhu1, Xiaohua Jie1, Yingzhuo Xu1, Xinrui Rao1, Yunhong Xu1, Yunshang Chen1, Biyuan Xing1, Gang Wu2, Liangliang Shi3. 1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. 2. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. sllhust@126.com. 3. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. xhzlwg@163.com.
Abstract
BACKGROUND: Programmed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear. METHODS: Bioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo. RESULTS: Bioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels. CONCLUSION: PD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.
BACKGROUND: Programmed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear. METHODS: Bioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo. RESULTS: Bioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels. CONCLUSION: PD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.
Authors: Aaron M Newman; Chih Long Liu; Michael R Green; Andrew J Gentles; Weiguo Feng; Yue Xu; Chuong D Hoang; Maximilian Diehn; Ash A Alizadeh Journal: Nat Methods Date: 2015-03-30 Impact factor: 28.547
Authors: 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; Meenhard Herlyn Journal: Nat Commun Date: 2021-01-12 Impact factor: 14.919