Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.
Nat Immunol
; 21(5): 555-566, 2020 05.
Article
in En
| MEDLINE
| ID: mdl-32327756
ABSTRACT
Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyruvaldehyde
/
CD8-Positive T-Lymphocytes
/
Myeloid-Derived Suppressor Cells
/
Immunotherapy
/
Melanoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2020
Document type:
Article
Affiliation country:
Alemania