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

Author

Listed:
  • Jae Eun Choi

    (University of Michigan
    University of Michigan
    University of California)

  • Yuanyuan Qiao

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Ilona Kryczek

    (University of Michigan
    University of Michigan)

  • Jiali Yu

    (University of Michigan
    University of Michigan)

  • Jonathan Gurkan

    (University of Michigan
    University of Michigan
    Northwestern University)

  • Yi Bao

    (University of Michigan
    University of Michigan)

  • Mahnoor Gondal

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Jean Ching-Yi Tien

    (University of Michigan
    University of Michigan)

  • Tomasz Maj

    (University of Michigan
    University of Michigan)

  • Sahr Yazdani

    (University of Michigan
    University of Michigan
    Children’s Hospital of Philadelphia)

  • Abhijit Parolia

    (University of Michigan
    University of Michigan)

  • Houjun Xia

    (University of Michigan
    University of Michigan)

  • JiaJia Zhou

    (University of Michigan
    University of Michigan)

  • Shuang Wei

    (University of Michigan
    University of Michigan)

  • Sara Grove

    (University of Michigan
    University of Michigan)

  • Linda Vatan

    (University of Michigan
    University of Michigan)

  • Heng Lin

    (University of Michigan
    University of Michigan)

  • Gaopeng Li

    (University of Michigan
    University of Michigan)

  • Yang Zheng

    (University of Michigan
    University of Michigan)

  • Yuping Zhang

    (University of Michigan
    University of Michigan)

  • Xuhong Cao

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Fengyun Su

    (University of Michigan
    University of Michigan)

  • Rui Wang

    (University of Michigan
    University of Michigan)

  • Tongchen He

    (University of Michigan
    University of Michigan)

  • Marcin Cieslik

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Michael D. Green

    (University of Michigan
    University of Michigan
    Department of Radiation Oncology Veterans Affairs Ann Arbor Healthcare System)

  • Weiping Zou

    (University of Michigan
    University of Michigan
    University of Michigan
    University of Michigan)

  • Arul M. Chinnaiyan

    (University of Michigan
    University of Michigan
    University of Michigan
    University of Michigan)

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.

Suggested Citation

  • 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 & Shua, 2024. "PIKfyve, expressed by CD11c-positive cells, controls tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48931-9
    DOI: 10.1038/s41467-024-48931-9
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