Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
Nat Immunol
; 25(3): 552-561, 2024 Mar.
Article
in En
| MEDLINE
| ID: mdl-38263463
ABSTRACT
The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Lithium Carbonate
/
Antimanic Agents
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Lactic Acid
/
Mitochondria
/
Neoplasms
Limits:
Humans
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: