PIKfyve, expressed by CD11c-positive cells, controls tumor immunity

Jae Eun Choi, Yuanyuan Qiao, Ilona Kryczek, Jiali Yu, Jonathan Gurkan, Yi Bao, Mahnoor Gondal, Jean Ching-Yi Tien, Tomasz Maj, Sahr Yazdani, Abhijit Parolia, Houjun Xia, JiaJia Zhou, Shuang Wei, Sara Grove, Linda Vatan, Heng Lin, Gaopeng Li, Yang Zheng, Yuping Zhang, Xuhong Cao, Fengyun Su, Rui Wang, Tongchen He, Marcin Cieslik, Michael D. Green, Weiping Zou () and Arul M. Chinnaiyan ()
Additional contact information
Jae Eun Choi: University of Michigan
Yuanyuan Qiao: University of Michigan
Ilona Kryczek: University of Michigan
Jiali Yu: University of Michigan
Jonathan Gurkan: University of Michigan
Yi Bao: University of Michigan
Mahnoor Gondal: University of Michigan
Jean Ching-Yi Tien: University of Michigan
Tomasz Maj: University of Michigan
Sahr Yazdani: University of Michigan
Abhijit Parolia: University of Michigan
Houjun Xia: University of Michigan
JiaJia Zhou: University of Michigan
Shuang Wei: University of Michigan
Sara Grove: University of Michigan
Linda Vatan: University of Michigan
Heng Lin: University of Michigan
Gaopeng Li: University of Michigan
Yang Zheng: University of Michigan
Yuping Zhang: University of Michigan
Xuhong Cao: University of Michigan
Fengyun Su: University of Michigan
Rui Wang: University of Michigan
Tongchen He: University of Michigan
Marcin Cieslik: University of Michigan
Michael D. Green: University of Michigan
Weiping Zou: University of Michigan
Arul M. Chinnaiyan: University of Michigan

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Date: 2024
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DOI: 10.1038/s41467-024-48931-9

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