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
786 0 _nCancer Res
856 4 1 _uhttp://dx.doi.org/10.1158/0008-5472.CAN-21-4052
_zConnect to this object online.
999 _c1594
_d1594