2. Academic Validation
  3. Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer

Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer

  • Cell Rep. 2025 Jan 28;44(1):115128. doi: 10.1016/j.celrep.2024.115128.
Ge Li 1,  Zhenke Wen 2,  Sidong Xiong 3
Affiliations

Affiliations

  • 1 The 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.
  • 2 The 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. Electronic address: zkwen@suda.edu.cn.
  • 3 The 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. Electronic address: sdxiong@suda.edu.cn.
PMID: 39754718 DOI: 10.1016/j.celrep.2024.115128
Abstract

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.

Keywords

CP: Cancer; CP: Immunology; NSCLC; T cell exhaustion; amino acid transport; β-TrCP.

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