Back to Search
Start Over
Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells
- Source :
- Journal of Clinical Investigation, Journal of Clinical Investigation, American Society for Clinical Investigation, 2010, 120 (2), pp.457-71. 〈10.1172/JCI40483〉, Journal of Clinical Investigation, American Society for Clinical Investigation, 2010, 120 (2), pp.457-71. ⟨10.1172/JCI40483⟩, Journal of Clinical Investigation, American Society for Clinical Investigation, 2020, ⟨10.1172/JCI40483⟩, Journal of Clinical Investigation, 2010, 120 (2), pp.457-71. ⟨10.1172/JCI40483⟩
- Publication Year :
- 2009
-
Abstract
- International audience; Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
- Subjects :
- MAPK/ERK pathway
MESH : Cell Line
[SDV]Life Sciences [q-bio]
T-Lymphocytes
HSP72 Heat-Shock Proteins
Exosomes
T-Lymphocytes, Regulatory
MESH: Amiloride
Amiloride
MESH : T-Lymphocytes, Regulatory
Mice
0302 clinical medicine
Neoplasms
[ SDV.IMM ] Life Sciences [q-bio]/Immunology
MESH: Animals
MESH: Neoplasms
ComputingMilieux_MISCELLANEOUS
MESH : Cyclophosphamide
0303 health sciences
education.field_of_study
MESH: Immunosuppression
MESH : Mice, Nude
General Medicine
3. Good health
Cell biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
[SDV.IMM]Life Sciences [q-bio]/Immunology
MESH : HSP72 Heat-Shock Proteins
Research Article
MESH: Cell Line, Tumor
[SDV.IMM] Life Sciences [q-bio]/Immunology
T cell
Population
Mice, Nude
Biology
Exosome
MESH: HSP72 Heat-Shock Proteins
Cell Line
03 medical and health sciences
MESH : Amiloride
Cell Line, Tumor
MESH : Mice
medicine
MESH: Mice, Nude
Animals
Humans
MESH: Exosomes
education
Autocrine signalling
MESH: Mice
Cyclophosphamide
030304 developmental biology
MESH : T-Lymphocytes
Immunosuppression Therapy
MESH: Humans
MESH : Cell Line, Tumor
MESH: T-Lymphocytes, Regulatory
MESH : Humans
MESH: Cyclophosphamide
MESH : Exosomes
MESH : Neoplasms
Microvesicles
MESH: Cell Line
TLR2
MESH: T-Lymphocytes
MESH : Immunosuppression
Myeloid-derived Suppressor Cell
MESH : Animals
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 120
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation
- Accession number :
- edsair.doi.dedup.....957db7380c2ec65e9aa92a1f12ae83b0