TY  - BOOK
AU  - Chowdhury,Snehanshu
AU  - Kar,Anwesha
AU  - Bhowmik,Debaleena
AU  - Gautam,Anupam
AU  - Basak,Debashree
AU  - Sarkar,Ishita
AU  - Ghosh,Puspendu
AU  - Sarkar,Deborpita
AU  - Deka,Alvina
AU  - Chakraborty,Paramita
AU  - Mukhopadhyay,Asima
AU  - Mehrotra,Shikhar
AU  - Basak,Soumen
AU  - Paul,Sandip
AU  - Chatterjee,Shilpak
TI  - Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8(+) T Cells
PY  - 2022///-07-18
PB  - American Association for Cancer Research, 
KW  - Text
KW  - local
N1  - /pmc/articles/PMC7613107; /pubmed/35648389
N2  - Effector 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
UR  - http://dx.doi.org/10.1158/0008-5472.CAN-21-4052
ER  -