RT Journal Article
SR Electronic
T1 Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti–PD-1/PD-L1 immunotherapy
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eaax7881
DO 10.1126/sciadv.aax7881
VO 6
IS 18
A1 Noman, Muhammad Zaeem
A1 Parpal, Santiago
A1 Van Moer, Kris
A1 Xiao, Malina
A1 Yu, Yasmin
A1 Arakelian, Tsolere
A1 Viklund, Jenny
A1 De Milito, Angelo
A1 Hasmim, Meriem
A1 Andersson, Martin
A1 Amaravadi, Ravi K.
A1 Martinsson, Jessica
A1 Berchem, Guy
A1 Janji, Bassam
YR 2020
UL http://advances.sciencemag.org/content/6/18/eaax7881.abstract
AB 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.