LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid
Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
|---|---|
| Enthalten in: |
International journal of molecular sciences - 23(2022), 11 vom: 26. Mai |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Decking, Sonja-Maria [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 13.06.2022 Date Revised 16.07.2022 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3390/ijms23115970 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM342043463 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM342043463 | ||
| 003 | DE-627 | ||
| 005 | 20231226013154.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/ijms23115970 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1140.xml |
| 035 | |a (DE-627)NLM342043463 | ||
| 035 | |a (NLM)35682650 | ||
| 035 | |a (PII)5970 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Decking, Sonja-Maria |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a LDHB Overexpression Can Partially Overcome T Cell Inhibition by Lactic Acid |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 13.06.2022 | ||
| 500 | |a Date Revised 16.07.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a LDH | |
| 650 | 4 | |a T cell metabolism | |
| 650 | 4 | |a T cells | |
| 650 | 4 | |a adoptive cell transfer | |
| 650 | 4 | |a glycolysis | |
| 650 | 4 | |a interferon gamma | |
| 650 | 4 | |a lactate | |
| 650 | 4 | |a lactic acid | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a Lactic Acid |2 NLM | |
| 650 | 7 | |a 33X04XA5AT |2 NLM | |
| 650 | 7 | |a Lactate Dehydrogenases |2 NLM | |
| 650 | 7 | |a EC 1.1.- |2 NLM | |
| 650 | 7 | |a L-Lactate Dehydrogenase |2 NLM | |
| 650 | 7 | |a EC 1.1.1.27 |2 NLM | |
| 650 | 7 | |a D-lactate dehydrogenase |2 NLM | |
| 650 | 7 | |a EC 1.1.1.28 |2 NLM | |
| 700 | 1 | |a Bruss, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Babl, Nathalie |e verfasserin |4 aut | |
| 700 | 1 | |a Bittner, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Klobuch, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Feuerer, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Hoffmann, Petra |e verfasserin |4 aut | |
| 700 | 1 | |a Dettmer, Katja |e verfasserin |4 aut | |
| 700 | 1 | |a Oefner, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Renner, Kathrin |e verfasserin |4 aut | |
| 700 | 1 | |a Kreutz, Marina |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International journal of molecular sciences |d 2008 |g 23(2022), 11 vom: 26. Mai |w (DE-627)NLM185552161 |x 1422-0067 |7 nnns |
| 773 | 1 | 8 | |g volume:23 |g year:2022 |g number:11 |g day:26 |g month:05 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ijms23115970 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 23 |j 2022 |e 11 |b 26 |c 05 | ||