Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity

Lauson, Carina B. Nava; Tiberti, Silvia; Corsetto, Paola Antonia; Conte, Federica; Tyagi, Punit; Machwirth, Markus; Ebert, Stefan; Loffreda, Alessia; Scheller, Lukas; Sheta, Dalia; Mokhtari, Zeinab; Peters, Timo; Raman, Ayush T.; Greco, Francesco; Rizzo, Angela; Beilhack, Andreas; Signore, Giovanni; Tumino, Nicola; Vacca, Paola; McDonnell, L.; Raimondi, Andrea; Greenberg, Philip D.; Huppa, Johannes B.; Cardaci, Simone; Caruana, Ignazio; Rodighiero, Simona; Nezi, Luigi; Manzo, Teresa

doi:10.1016/j.cmet.2023.02.013

Cited by 72 publications

(38 citation statements)

References 134 publications

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“…33 Ma et al 34 indicated that arachidonic acid, a polyunsaturated fatty acid, decreases IFN-γ production by CD8 + T cells via increased lipid peroxidation and ferroptosis. Nava Lauson et al 35 reported that linoleic acid is a major positive regulator of CD8 + T cell effector functions via improving mitochondrial fitness and preventing exhaustion. Recent reports also indicated that intracellular cholesterol also plays a major role in the regulation of T cell antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

SCD1 inhibition enhances the effector functions of CD8⁺ T cells via ACAT1‐dependent reduction of esterified cholesterol

Sugi,

Katoh,

Ikeda

et al. 2023

Cancer Science

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We previously reported that the inhibition of stearoyl‐CoA desaturase 1 (SCD1) enhances the antitumor function of CD8+ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8+ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8+ T cells. In vitro treatment of CD8+ T cells with SCD1 inhibitors enhanced IFN‐γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl‐CoA acetyltransferase 1 (ACAT1), in CD8+ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8+ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor‐bearing mice enhanced IFN‐γ production of tumor‐infiltrating CD8+ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8+ T cells through the increased esterified cholesterol in an ACAT1‐dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti‐PD‐1 antibody therapy or CAR‐T cell therapy in mouse tumor models. Therefore, the SCD1–ACAT1 axis is regulating effector functions of CD8+ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

SCD1 inhibition enhances the effector functions of CD8⁺ T cells via ACAT1‐dependent reduction of esterified cholesterol

Sugi,

Katoh,

Ikeda

et al. 2023

Cancer Science

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“…Furthermore, it has recently been reported that dietary PUFAs induce ferroptosis in cancer cells via lipid peroxidation ( 45 , 46 ). Although PUFA supplementation has shown a direct antitumor effect, the role of PUFAs in tumor immunity is controversial as PUFAs have been shown to not only promote stromal cell–mediated immunosuppression ( 47 , 48 ) but also potentiate CD8 + T cell–mediated antitumor immunity ( 49 , 50 ). In addition, whether and how PUFA supplementation affects tumor cell metabolism to further regulate antitumor immune responses is largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation

Xiang,

Lv,

Xing

et al. 2023

Sci. Adv.

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Adenosine 5′-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl–coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti–PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.

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“…[36] Furthermore, memory T cells exhibit a metabolic preference for oxidizing long-chain fatty acids (LCFAs). [15,37,38] AMPK is involved in regulating LCFAs uptake and memory T cell differentiation, promoting the expression of CPT1α by inhibiting acetyl-CoA carboxylase 2 (ACC2), which converts acetyl-CoA to malonyl-CoA. [39] This process augments the oxidation of LCFAs and promotes the formation of memory T cells.…”

Section: Glucose Metabolismmentioning

confidence: 99%

Metabolic plasticity of T cell fate decision

Pan,

Wang,

Zhang

et al. 2024

Chinese Medical Journal

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The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells. Upon antigen exposure, T cells undergo metabolic reprogramming, leading to the development of functional effectors or memory populations. However, within the tumor microenvironment (TME), metabolic stress impairs CD8+ T cell anti-tumor immunity, resulting in exhausted differentiation. Recent studies suggest that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy. In this review, we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions. Furthermore, we delved into the different metabolic switches that occur during T cell exhaustion, exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion, ultimately leading to a persistently exhausted state. Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.

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Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity

Cited by 72 publications

References 134 publications

SCD1 inhibition enhances the effector functions of CD8⁺ T cells via ACAT1‐dependent reduction of esterified cholesterol

SCD1 inhibition enhances the effector functions of CD8⁺ T cells via ACAT1‐dependent reduction of esterified cholesterol

Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation

Metabolic plasticity of T cell fate decision

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Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity

Cited by 72 publications

References 134 publications

SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1‐dependent reduction of esterified cholesterol

SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1‐dependent reduction of esterified cholesterol

Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation

Metabolic plasticity of T cell fate decision

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SCD1 inhibition enhances the effector functions of CD8⁺ T cells via ACAT1‐dependent reduction of esterified cholesterol

SCD1 inhibition enhances the effector functions of CD8⁺ T cells via ACAT1‐dependent reduction of esterified cholesterol