Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8(+) T Cells (Record no. 1744)
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042 ## - AUTHENTICATION CODE | |
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Authentication code | dc |
100 10 - MAIN ENTRY--PERSONAL NAME | |
Personal name | Chowdhury, Snehanshu |
Relator term | author |
9 (RLIN) | 1183 |
245 00 - TITLE STATEMENT | |
Title | Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8(+) T Cells |
260 ## - PUBLICATION, DISTRIBUTION, ETC. | |
Name of publisher, distributor, etc. | American Association for Cancer Research, |
Date of publication, distribution, etc. | 2022-07-18. |
500 ## - GENERAL NOTE | |
General note | /pmc/articles/PMC7613107/ |
500 ## - GENERAL NOTE | |
General note | /pubmed/35648389 |
520 ## - SUMMARY, ETC. | |
Summary, etc. | 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. |
540 ## - TERMS GOVERNING USE AND REPRODUCTION NOTE | |
Terms governing use and reproduction | ©2022 The Authors; Published by the American Association for Cancer Research |
540 ## - TERMS GOVERNING USE AND REPRODUCTION NOTE | |
Terms governing use and reproduction | https://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 ## - LANGUAGE NOTE | |
Language note | en |
690 ## - LOCAL SUBJECT ADDED ENTRY--TOPICAL TERM (OCLC, RLIN) | |
Topical term or geographic name as entry element | Tumor Biology and Immunology |
9 (RLIN) | 1198 |
655 7# - INDEX TERM--GENRE/FORM | |
Genre/form data or focus term | Text |
Source of term | local |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Kar, Anwesha |
Relator term | author |
9 (RLIN) | 1184 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Bhowmik, Debaleena |
Relator term | author |
9 (RLIN) | 1185 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Gautam, Anupam |
Relator term | author |
9 (RLIN) | 1186 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Basak, Debashree |
Relator term | author |
9 (RLIN) | 1187 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Sarkar, Ishita |
Relator term | author |
9 (RLIN) | 1188 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Ghosh, Puspendu |
Relator term | author |
9 (RLIN) | 1189 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Sarkar, Deborpita |
Relator term | author |
9 (RLIN) | 1190 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Deka, Alvina |
Relator term | author |
9 (RLIN) | 1191 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Chakraborty, Paramita |
Relator term | author |
9 (RLIN) | 1192 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Mukhopadhyay, Asima |
Relator term | author |
9 (RLIN) | 1193 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Mehrotra, Shikhar |
Relator term | author |
9 (RLIN) | 1194 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Basak, Soumen |
Relator term | author |
9 (RLIN) | 1195 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Paul, Sandip |
Relator term | author |
9 (RLIN) | 1196 |
700 10 - ADDED ENTRY--PERSONAL NAME | |
Personal name | Chatterjee, Shilpak |
Relator term | author |
9 (RLIN) | 1197 |
786 0# - DATA SOURCE ENTRY | |
Note | Cancer Res |
856 41 - ELECTRONIC LOCATION AND ACCESS | |
Uniform Resource Identifier | <a href="http://dx.doi.org/10.1158/0008-5472.CAN-21-4052">http://dx.doi.org/10.1158/0008-5472.CAN-21-4052</a> |
Public note | Connect to this object online. |
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