Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti-PD-1/PD-L1 immunotherapy

Muhammad Zaeem Noman, Santiago Parpal, Kris van Moer, Malina Xiao, Yasmin Yu, Jenny Viklund, Angelo de Milito, Meriem Hasmim, Martin Andersson, Ravi K. Amaravadi, Jessica Martinsson, Guy Berchem, Bassam Janji*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

134 Citations (Scopus)


One of the major challenges limiting the efficacy of anti-PD-1/PD-L1 therapy in nonresponding patients is the failure of T cells to penetrate the tumor microenvironment. We showed that genetic or pharmacological inhibition of Vps34 kinase activity using SB02024 or SAR405 (Vps34i) decreased the tumor growth and improved mice survival in multiple tumor models by inducing an infiltration of NK, CD8+, and CD4+ T effector cells in melanoma and CRC tumors. Such infiltration resulted in the establishment of a T cell−inflamed tumor microenvironment, characterized by the up-regulation of pro-inflammatory chemokines and cytokines, CCL5, CXCL10, and IFNγ. Vps34i treatment induced STAT1 and IRF7, involved in the up-regulation of CCL5 and CXCL10. Combining Vps34i improved the therapeutic benefit of anti-PD-L1/PD-1 in melanoma and CRC and prolonged mice survival. Our study revealed that targeting Vps34 turns cold into hot inflamed tumors, thus enhancing the efficacy of anti-PD-L1/PD-1 blockade.

Original languageEnglish
Article numbereaax7881
JournalScience advances
Issue number18
Publication statusPublished - Apr 2020


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