Dataset Information

Label-free proteome analysis of small extracellular vesicles (sEV) expressing different HRS mutants.

ABSTRACT: Label-free proteome analysis of small extracellular vesicles (sEV) derived from WM9 cells expressing different HRS mutants: wild type (HRSWT), phospho-deficient (HRSS345A), and phospho-mimetic mutant HRS (HRSS345D).

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Wei guo David W. Speicher

PROVIDER: MSV000088846 | MassIVE | Wed Feb 16 06:31:00 GMT 2022

SECONDARY ACCESSION(S): PXD031715

REPOSITORIES: MassIVE

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Publications

HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors.

Guan Lei L Wu Bin B Li Ting T Beer Lynn A LA Sharma Gaurav G Li Mingyue M Lee Chin Nien CN Liu Shujing S Yang Changsong C Huang Lili L Frederick Dennie T DT Boland Genevieve M GM Shao Guangcan G Svitkina Tatyana M TM Cai Kathy Q KQ Chen Fangping F Dong Meng-Qiu MQ Mills Gordon B GB Schuchter Lynn M LM Karakousis Giorgos C GC Mitchell Tara C TC Flaherty Keith T KT Speicher David W DW Chen Youhai H YH Herlyn Meenhard M Amaravadi Ravi K RK Xu Xiaowei X Guo Wei W

Nature communications 20220714 1

The lack of tumor infiltration by CD8+ T cells is associated with poor patient response to anti-PD-1 therapy. Understanding how tumor infiltration is regulated is key to improving treatment efficacy. Here, we report that phosphorylation of HRS, a pivotal component of the ESCRT complex involved in exosome biogenesis, restricts tumor infiltration of cytolytic CD8+ T cells. Following ERK-mediated phosphorylation, HRS interacts with and mediates the selective loading of PD-L1 t ...[more]

PMID: 35835783

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Project description:Background: Allergic asthma is one of the chronic inflammatory diseases and is generally induced by CD4+ T helper 2 cells (Th2) in the context of persistent inhaled stimuli. Dendritic cells (DCs) are essential to mounting the Th2-mediated airway inflammation by presenting inhaled antigens to prime CD4+ T cells. Small extracellular vesicles (sEV) derived from mesenchymal stem cells (MSCs) exhibited great interest in intractable diseases. However, whether MSC-sEV play a role on DCs in airway inflammation is still unclear. Methods: We isolate MSC-sEV using anion-exchange chromatography. Mouse bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs (moDCs) were used to study the effects of MSC-sEV on dendritic cell surface molecules and their cytokine release. Mice were sensitized with house dust mites (HDM) to induce airway inflammation, and treated with MSC-sEV, The effects of sEV on murine DCs were identified. Extracellular flux analysis techniques were used to study the effects of MSC-sEV on the metabolic state of dendritic cells. RNA sequencing to study altered gene expression in BMDCs after MSC-sEV treatment. Results: MSC-sEV mitigated the accumulation of Th2-associated moDCs in mouse lung in response to HDM. MSC-sEV also decreased the activation of moDCs induced in vitro including the expression of co-stimulatory molecules and cytokines secretion. Furthermore, we identified that DCs were able to take MSC-sEV in vitro and in vivo. Mechanistically, using bulk RNA-sequencing, we found that MSC-sEV played roles in the metabolic pathway of murine DCs. Using extracellular flux analysis, we found that MSC-sEV increased the requirement of oxidative phosphorylation on moDCs. Importantly, MSC-sEV displayed similar effects on human moDCs including decreased co-stimulatory molecular and cytokine production. Conclusions: MSC-sEV are able to alter the metabolic state of DCs, favoring DCs to maintain OXPHOS (oxidative phosphorylation) rather than glycolysis, thereby reducing DCs-initiated inflammatory responses and attenuating Th2 lung inflammation, suggesting MSC-sEV can be a potential clinical therapy for airway inflammation.

Dataset Information

Label-free proteome analysis of small extracellular vesicles (sEV) expressing different HRS mutants.

Dataset's files

Publications

HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8<sup>+</sup> T-cell infiltration into tumors.

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