The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells
Open accessAbstract
CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.
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Cites
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Lipid metabolism in cancer: New perspectives and emerging mechanisms
Broadfield, L. A., Pane, A. A., Talebi, A., Swinnen, J. V., & Fendt, S.-M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.04.013 · Cited by 758
Tumor-infiltrating regulatory T cells as targets of cancer immunotherapy
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Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity
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“Lipid accumulation in the TME of a pancreatic cancer model led to intracellular lipid accumulation in CD8 T cells, reducing their functionality (Manzo et al., 2020).”
Background
Metadata
- Authors
- Manzo, T., Prentice, B. M., Anderson, K. G., Raman, A., Schalck, A., Codreanu, G. S., Nava Lauson, C. B., Tiberti, S., Raimondi, A., Jones, M. A., Reyzer, M., Bates, B. M., Spraggins, J. M., Patterson, N. H., McLean, J. A., Rai, K., Tacchetti, C., Tucci, S., Wargo, J. A., Rodighiero, S., Clise-Dwyer, K., Sherrod, S. D., Kim, M., Navin, N. E., Caprioli, R. M., Greenberg, P. D., Draetta, G., & Nezi, L.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2020-06-03
- Volume
- 217
- Issue
- 8
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W3028703234
- Cited by
- 342
- References
- 27
- FWCI
- 10.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Manzo, T., Prentice, B. M., Anderson, K. G., Raman, A., Schalck, A., Codreanu, G. S., Nava Lauson, C. B., Tiberti, S., Raimondi, A., Jones, M. A., Reyzer, M., Bates, B. M., Spraggins, J. M., Patterson, N. H., McLean, J. A., Rai, K., Tacchetti, C., Tucci, S., Wargo, J. A., . . . Nezi, L. (2020). Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20191920
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
