| 000 | 03424 am a22003733u 4500 | ||
|---|---|---|---|
| 042 | _adc | ||
| 100 | 1 | 0 |
_aChowdhury, Snehanshu _eauthor _91183 |
| 700 | 1 | 0 |
_aKar, Anwesha _eauthor _91184 |
| 700 | 1 | 0 |
_aBhowmik, Debaleena _eauthor _91185 |
| 700 | 1 | 0 |
_aGautam, Anupam _eauthor _91186 |
| 700 | 1 | 0 |
_aBasak, Debashree _eauthor _91187 |
| 700 | 1 | 0 |
_aSarkar, Ishita _eauthor _91188 |
| 700 | 1 | 0 |
_aGhosh, Puspendu _eauthor _91189 |
| 700 | 1 | 0 |
_aSarkar, Deborpita _eauthor _91190 |
| 700 | 1 | 0 |
_aDeka, Alvina _eauthor _91191 |
| 700 | 1 | 0 |
_aChakraborty, Paramita _eauthor _91192 |
| 700 | 1 | 0 |
_aMukhopadhyay, Asima _eauthor _91193 |
| 700 | 1 | 0 |
_aMehrotra, Shikhar _eauthor _91194 |
| 700 | 1 | 0 |
_aBasak, Soumen _eauthor _91195 |
| 700 | 1 | 0 |
_aPaul, Sandip _eauthor _91196 |
| 700 | 1 | 0 |
_aChatterjee, Shilpak _eauthor _91197 |
| 245 | 0 | 0 | _aIntracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8(+) T Cells |
| 260 |
_bAmerican Association for Cancer Research, _c2022-07-18. |
||
| 500 | _a/pmc/articles/PMC7613107/ | ||
| 500 | _a/pubmed/35648389 | ||
| 520 | _aEffector CD8(+) T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T-cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust antitumor immune response. Here, we report that IL12-stimulated CD8(+) T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumor-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose-citrate-acetyl CoA circuit in IL12-stimulated CD8(+) T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8(+) T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8(+) T cells in nutrient-restricted conditions. Furthermore, CD8(+) T cells cultured in high pyruvate-containing media in vitro acquired critical metabolic features of IL12-stimulated CD8(+) T cells and displayed improved antitumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8(+) T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8(+) T cells for adoptive T-cell therapy. SIGNIFICANCE: IL12-mediated metabolic reprogramming increases intracellular acetyl CoA to promote the effector function of CD8(+) T cells in nutrient-depleted tumor microenvironments, revealing strategies to potentiate the antitumor efficacy of T cells. | ||
| 540 | _a©2022 The Authors; Published by the American Association for Cancer Research | ||
| 540 | _ahttps://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. | ||
| 546 | _aen | ||
| 690 |
_aTumor Biology and Immunology _91198 |
||
| 655 | 7 |
_aText _2local |
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| 786 | 0 | _nCancer Res | |
| 856 | 4 | 1 |
_uhttp://dx.doi.org/10.1158/0008-5472.CAN-21-4052 _zConnect to this object online. |
| 999 |
_c1744 _d1744 |
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