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; Arul M Chinnaiyan

doi:10.1038/s41467-024-48931-9

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

Nat Commun. 2024 Jun 28;15(1):5487. doi: 10.1038/s41467-024-48931-9.

Authors

Jae Eun Choi^{1

2

3}, Yuanyuan Qiao^{1

2

4}, Ilona Kryczek^{5

6}, Jiali Yu^{5

6}, Jonathan Gurkan^{1

2

7}, Yi Bao^{1

2}, Mahnoor Gondal^{1

2

8}, Jean Ching-Yi Tien^{1

2}, Tomasz Maj^{5

6}, Sahr Yazdani^{1

2

9}, Abhijit Parolia^{1

2}, Houjun Xia^{5

6}, JiaJia Zhou^{5

6}, Shuang Wei^{5

6}, Sara Grove^{5

6}, Linda Vatan^{5

6}, Heng Lin^{5

6}, Gaopeng Li^{5

6}, Yang Zheng^{1

2}, Yuping Zhang^{1

2}, Xuhong Cao^{1

2

10}, Fengyun Su^{1

2}, Rui Wang^{1

2}, Tongchen He^{1

2}, Marcin Cieslik^{1

2

8}, Michael D Green^{6

11

12}, Weiping Zou^{13

14

15

16

17}, Arul M Chinnaiyan^{18

19

20

21

22}

Affiliations

¹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
² Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Pediatrics, University of California, San Francisco, CA, USA.
⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
⁶ Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA.
⁷ Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁸ Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Radiation Oncology Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA.
¹³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA. [email protected].
¹⁴ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. [email protected].
¹⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. [email protected].
¹⁶ Department of Surgery, University of Michigan, Ann Arbor, MI, USA. [email protected].
¹⁷ Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA. [email protected].
¹⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA. [email protected].
¹⁹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. [email protected].
²⁰ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. [email protected].
²¹ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA. [email protected].
²² Department of Urology, University of Michigan, Ann Arbor, MI, USA. [email protected].

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.

MeSH terms

Animals
CD11c Antigen* / metabolism
Cell Line, Tumor
Dendritic Cells* / drug effects
Dendritic Cells* / immunology
Dendritic Cells* / metabolism
Female
Humans
Hydrazones
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Immunotherapy / methods
Male
Mice
Mice, Inbred C57BL
Morpholines* / pharmacology
NF-kappa B / metabolism
Neoplasms / genetics
Neoplasms / immunology
Neoplasms / therapy
Phosphatidylinositol 3-Kinases* / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pyrimidines
T-Lymphocytes / immunology

Substances

apilimod
CD11c Antigen
Hydrazones
Immune Checkpoint Inhibitors
Morpholines
NF-kappa B
Phosphatidylinositol 3-Kinases
PIKFYVE protein, human
Protein Kinase Inhibitors
Pyrimidines
Pikfyve protein, mouse

Abstract

MeSH terms

Substances

Grants and funding