Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 49; p. e2314416120
• Main Authors: Bao, Yi, Qiao, Yuanyuan, Choi, Jae Eun, Zhang, Yuping, Mannan, Rahul, Cheng, Caleb, He, Tongchen, Zheng, Yang, Yu, Jiali, Gondal, Mahnoor, Cruz, Gabriel, Grove, Sara, Cao, Xuhong, Su, Fengyun, Wang, Rui, Chang, Yu, Kryczek, Ilona, Cieslik, Marcin, Green, Michael D, Zou, Weiping, Chinnaiyan, Arul M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.12.2023
• Subjects: Animal models; Animals; Antitumor activity; Biological Sciences; Cancer; Cancer immunotherapy; CD8 antigen; CD8-Positive T-Lymphocytes; Cell therapy; Depletion; Genes, MHC Class I; Histocompatibility Antigens Class I; Humans; Immune checkpoint inhibitors; Immunotherapy; Immunotherapy - methods; Kinases; Lipid kinase; Lipids; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mice; Neoplasms - genetics; Neoplasms - therapy; Patients; Pharmacology; Tumors; Vaccines; MHC class I; PIKfyve; cancer; immunotherapy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2314416120

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8 T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8 T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by -depletion were CD8 T cell- and MHC-I-dependent, as CD8 T cell depletion or knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.