Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer
Summary: CD8+ T cell exhaustion (Tex) has been widely acknowledged in human cancer, while the underlying mechanisms remain unclear. Here, we demonstrate that reduced amino acid (aa) metabolism and mTOR inactivation are accountable for Tex in human non-small cell lung cancer (NSCLC). NSCLC cells impe...
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014797 |
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| author | Ge Li Zhenke Wen Sidong Xiong |
| author_facet | Ge Li Zhenke Wen Sidong Xiong |
| author_sort | Ge Li |
| collection | DOAJ |
| description | Summary: CD8+ T cell exhaustion (Tex) has been widely acknowledged in human cancer, while the underlying mechanisms remain unclear. Here, we demonstrate that reduced amino acid (aa) metabolism and mTOR inactivation are accountable for Tex in human non-small cell lung cancer (NSCLC). NSCLC cells impede the T cell-intrinsic transcription of SLC7A5 and SLC38A1, disrupting aa transport and consequently leading to mTOR inactivation. Further, the ubiquitination of YAP1 protein is the basis for NSCLC-mediated transcriptional inhibition of aa transporters. Mechanistically, NSCLC cells transfer β-TrCP-containing exosomes into T cells, inducing YAP1 ubiquitination and Tex. Consequently, inhibiting cancer-associated β-TrCP effectively restores the anti-tumor immune response of CD8+ T cells and curtails tumor growth in NSCLC patient-derived organoids. Together, our findings highlight a β-TrCP-dependent mechanism in steering intrinsic metabolic adaptation and CD8+ Tex, emphasizing microenvironmental β-TrCP as an immune checkpoint for therapeutic exploration against human NSCLC. |
| format | Article |
| id | doaj-art-cad3f33f31df47f6891894fc11f131cf |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-cad3f33f31df47f6891894fc11f131cf2025-01-04T04:56:16ZengElsevierCell Reports2211-12472025-01-01441115128Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancerGe Li0Zhenke Wen1Sidong Xiong2The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, ChinaThe Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China; Corresponding authorThe Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China; Corresponding authorSummary: CD8+ T cell exhaustion (Tex) has been widely acknowledged in human cancer, while the underlying mechanisms remain unclear. Here, we demonstrate that reduced amino acid (aa) metabolism and mTOR inactivation are accountable for Tex in human non-small cell lung cancer (NSCLC). NSCLC cells impede the T cell-intrinsic transcription of SLC7A5 and SLC38A1, disrupting aa transport and consequently leading to mTOR inactivation. Further, the ubiquitination of YAP1 protein is the basis for NSCLC-mediated transcriptional inhibition of aa transporters. Mechanistically, NSCLC cells transfer β-TrCP-containing exosomes into T cells, inducing YAP1 ubiquitination and Tex. Consequently, inhibiting cancer-associated β-TrCP effectively restores the anti-tumor immune response of CD8+ T cells and curtails tumor growth in NSCLC patient-derived organoids. Together, our findings highlight a β-TrCP-dependent mechanism in steering intrinsic metabolic adaptation and CD8+ Tex, emphasizing microenvironmental β-TrCP as an immune checkpoint for therapeutic exploration against human NSCLC.http://www.sciencedirect.com/science/article/pii/S2211124724014797CP: ImmunologyCP: Cancer |
| spellingShingle | Ge Li Zhenke Wen Sidong Xiong Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer Cell Reports CP: Immunology CP: Cancer |
| title | Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer |
| title_full | Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer |
| title_fullStr | Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer |
| title_full_unstemmed | Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer |
| title_short | Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer |
| title_sort | microenvironmental β trcp negates amino acid transport to trigger cd8 t cell exhaustion in human non small cell lung cancer |
| topic | CP: Immunology CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014797 |
| work_keys_str_mv | AT geli microenvironmentalbtrcpnegatesaminoacidtransporttotriggercd8tcellexhaustioninhumannonsmallcelllungcancer AT zhenkewen microenvironmentalbtrcpnegatesaminoacidtransporttotriggercd8tcellexhaustioninhumannonsmallcelllungcancer AT sidongxiong microenvironmentalbtrcpnegatesaminoacidtransporttotriggercd8tcellexhaustioninhumannonsmallcelllungcancer |