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CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via JAK2/STAT3 pathway

Canhui Cao1, Miaochun Xu2, Ye Wei1

  • 1Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430199, China; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.

Cell Genomics
|September 24, 2024
PubMed

Insights

CXCR4 antagonists can improve cancer immunotherapy. This study reveals CXCR4 drives T-cell exhaustion, and blocking it restores immune function, supporting combination therapies.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Clinical trials indicate CXCR4 antagonists enhance cancer immunotherapy.
  • The precise mechanisms of CXCR4's role in immune cell phenotypes remain unclear.

Purpose of the Study:

  • To elucidate the role of CXCR4 in CD8+ T-cell exhaustion.
  • To investigate the mechanistic pathways regulated by CXCR4 in T-cells.
  • To provide a rationale for CXCR4 antagonist combination therapy.

Main Methods:

  • Single-cell transcriptomic analysis (scRNA-seq).
  • In vivo experiments blocking CXCR4.
  • Single-cell RNA/TCR/ATAC-seq.
  • Clinical sample analysis.

Main Results:

  • CXCR4 is a marker gene in T-cells, highly expressed in exhausted CD8+ T (Tex) cells.
  • Blocking CXCR4 in vivo attenuated the Tex phenotype.
  • CXCR4 blockade modulated the JAK2-STAT3 pathway.
  • Cxcr4-deficient CD8+ T-cells showed epigenetic mitigation of exhaustion.
  • Increased CXCR4+CD8+ T-cells correlated with non-complete pathological response in patients.

Conclusions:

  • CXCR4 orchestrates the CD8+ Tex cell phenotype.
  • CXCR4 antagonists can reverse T-cell exhaustion via the JAK2-STAT3 pathway.
  • These findings support combining CXCR4 antagonists with immunotherapy for enhanced efficacy.
Keywords:
CD8 T cellsCXCR4JAK2-STAT3 pathwayPD-1T cell exhaustionimmune checkpoint blockadeimmunotherapysingle-cell ATAC-seqsingle-cell RNA-seqtumor microenvironment

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