Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

Manzo, Teresa; Prentice, Boone M.; Anderson, Kristin G.; Raman, Ayush T.; Schalck, Aislyn; Codreanu, Gabriela S.; Lauson, Carina B. Nava; Tiberti, Silvia; Raimondi, Andrea; Jones, Marissa A.; Reyzer, Michelle L.; Bates, Breanna M.; Spraggins, Jeffrey M.; Patterson, Nathan Heath; McLean, John A.; Rai, Kunal; Tacchetti, Carlo; Tucci, Sara; Wargo, Jennifer A.; Rodighiero, Simona; Clise-Dwyer, Karen; Sherrod, Stacy D.; Kim, Michael; Navin, Nicholas E.; Caprioli, Richard M.; Greenberg, Philip D.; Draetta, Giulio; Nezi, Luigi

doi:10.1084/jem.20191920

Cited by 204 publications

(186 citation statements)

References 107 publications

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“…Elevated fatty acid levels promote the differentiation of CD4 + T cells toward an effector-memory-like phenotype in obesity ( Mauro et al, 2017 ) and suppress the NK cell-mediated anti-tumor response through the accumulation of intracellular lipids ( Michelet et al, 2018 ). 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 ). Enabling the T cells to use these lipids for oxidation restored T cell function.…”

Section: Introductionmentioning

confidence: 99%

The effects of age and systemic metabolism on anti-tumor T cell responses

Drijvers

Sharpe

Haigis

2020

eLife

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Average age and obesity prevalence are increasing globally. Both aging and obesity are characterized by profound systemic metabolic and immunologic changes and are cancer risk factors. The mechanisms linking age and body weight to cancer are incompletely understood, but recent studies have provided evidence that the anti-tumor immune response is reduced in both conditions, while responsiveness to immune checkpoint blockade, a form of cancer immunotherapy, is paradoxically intact. Dietary restriction, which promotes health and lifespan, may enhance cancer immunity. These findings illustrate that the systemic context can impact anti-tumor immunity and immunotherapy responsiveness. Here, we review the current knowledge of how age and systemic metabolic state affect the anti-tumor immune response, with an emphasis on CD8+ T cells, which are key players in anti-tumor immunity. A better understanding of the underlying mechanisms may lead to novel therapies enhancing anti-tumor immunity in the context of aging or metabolic dysfunction.

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Section: Introductionmentioning

confidence: 99%

The effects of age and systemic metabolism on anti-tumor T cell responses

Drijvers

Sharpe

Haigis

2020

eLife

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“…Deregulated lipid metabolism is a common feature of the TME, and increased lipid uptake and accumulation is observed in many types of intratumoral immune cells, often associated with impaired anti-tumor immune function (Herber et al, 2010;Manzo et al, 2020;Su et al, 2020;Veglia et al, 2019;Zhang et al, 2017). Consistent with our findings, intratumoral CD8 + TILs in pancreatic cancers increase lipid deposition, specifically very-long chain fatty acids (VLCFAs) (Manzo et al, 2020). The metabolic fitness of intratumoral Tregs depends on enhanced CD36 expression for heightened lipid uptake and accumulation, and CD36-deficient Tregs had lower amounts of mitochondria specifically in tumors .…”

Section: Discussionmentioning

confidence: 99%

“…Several reports have shown that immune cells often have increased lipid content associated with abnormal functions in tumors, which could arise via increased de novo lipogenesis or import (Al-Khami et al, 2017;Ma et al, 2019;Manzo et al, 2020;Veglia et al, 2019;Zhang et al, 2017). To better understand what types of lipids immune cells are exposed to and could potentially import in tumors, we profiled the composition and abundance of various lipids within tumor interstitial fluid (TIF), which can be considered a proxy of the 'extracellular milieu' of the TME, from B16 or MC38 implanted tumors.…”

Section: Cd8 Tils Adapt To Increased Lipid Abundance In the Tmementioning

confidence: 99%

“…Tumor-associated macrophages increase lipid accumulation and in an in vitro co-culture system, tumor cells induce neutral lipid storage and FAO in macrophages (Su et al, 2020). Additionally, accumulation of very long chain fatty acids or cholesterol has been shown to induce CD8 + TIL dysfunction (i.e., reduced cytotoxicity and TNF and IFNg cytokine production), which is commonly referred to as T cell "exhaustion" (Ma et al, 2019;Manzo et al, 2020;Schietinger et al, 2016;Zajac et al, 1998). Lastly, increased lipid uptake in intratumoral regulatory CD4 + T cells (Tregs) promotes their maintenance and suppressive functions (Pacella et al, 2018;.…”

Section: Introductionmentioning

confidence: 99%

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Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

Chaudhary

Rodríguez-Morales

et al. 2020

Preprint

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T cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction (i.e., exhaustion) in cancer. We identify that the scavenger receptor CD36 limits anti-tumor CD8+ T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+ TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally exhausted CD8+ TILs substantially increased CD36 expression and CD36-deficient CD8+ TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL) and induces lipid peroxidation in CD8+ TILs, and OxLDL inhibits CD8+ T cell functions in a CD36-dependent manner. Moreover, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+ TILs. These results define a key role for an oxidized lipid-CD36 axis in promoting intratumoral CD8+ T cell dysfunction.

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“…TME serves a vital role in the development of pancreatic cancer ( 61 ). Additionally, it is the leading cause of chemotherapy resistance in patients with pancreatic cancer, as well as poor prognosis ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of prognostic immune‑related genes associated with the tumor microenvironment of pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a specific tumor immune microenvironment (TIME). Therefore, investigating prognostic immune-related genes (IRGs) that are closely associated with TIME to predict PDAC clinical outcomes is necessary. In the present study, 459 samples of PDAC from the Genotype-Tissue Expression database, The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) were included and a survival-associated module was identified using weighted gene co-expression network analysis. Based on the Cox regression analysis and least absolute shrinkage and selection operator analysis, four IRGs (2′-5′-oligoadenylate synthetase 1, MET proto-oncogene, receptor tyrosine kinase, interleukin 1 receptor type 2 and interleukin 20 receptor subunit β) were included in the prognostic model to calculate the risk score (RS), and patients with PDAC were divided into high- and low-RS groups. Kaplan-Meier survival and receiver operating characteristic curve analyses demonstrated that the low-RS group had significantly improved survival conditions compared with the high-RS group in TCGA training set. The prognostic function of the model was also validated using ICGC and GEO cohorts. To investigate the mechanism of different overall survival between the high- and low-RS groups, the present study included Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data and Cell Type Identification by Estimating Relative Subset of Known RNA Transcripts algorithms to investigate the state of the tumor microenvironment and immune infiltration inpatients in the cohort from TCGA. In summary, four genes associated with the TIME of PDAC were identified, which may provide a reference for clinical treatment.

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Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

Cited by 204 publications

References 107 publications

The effects of age and systemic metabolism on anti-tumor T cell responses

The effects of age and systemic metabolism on anti-tumor T cell responses

Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

Comprehensive analysis of prognostic immune‑related genes associated with the tumor microenvironment of pancreatic ductal adenocarcinoma

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