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PD-1 Inhibits CD4+ TRM-Mediated cDC1 Mobilization via Suppressing JAML in Human NSCLC
Zheyu Shao1,2, Qinyuan Liu1,2, Zhongwei Xin3
1Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 4, 2026
Summary
Tissue-resident memory CD4+ T cells (CD4+ TRMs) in lung cancer recruit dendritic cells to fight tumors. Targeting JAML enhances anti-PD-1 therapy effectiveness by restoring CD4+ TRM function.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Tissue-resident memory CD4+ T cells (CD4+ TRMs) are crucial for immunity but their role in the tumor microenvironment (TME) is unclear.
- Non-small cell lung cancer (NSCLC) TME presents unique challenges for immune surveillance and response.
Purpose of the Study:
- To define the phenotype and function of CD4+ TRMs in NSCLC.
- To investigate the mechanisms of CD4+ TRM-mediated anti-tumor immunity.
- To explore therapeutic strategies targeting CD4+ TRMs in NSCLC.
Main Methods:
- Flow cytometry and transcriptional profiling to characterize tumor-infiltrating CD4+ TRMs.
- Murine models of NSCLC to study CD4+ TRM function and therapeutic interventions.
- Analysis of clinical NSCLC patient data to correlate CD4+ TRM presence with outcomes.
Main Results:
- NSCLC CD4+ TRMs resemble murine models and recruit dendritic cells via XCL1 secretion.
- JAML is essential for CD4+ TRM-mediated dendritic cell recruitment.
- Tumor-infiltrating CD4+ TRMs show immune dysfunction, with reduced XCL1 and suppressed JAML by PD-1.
- PD-1 blockade and JAML agonists enhance anti-tumor immunity in mice.
- XCL1+ CD4+ TRMs correlate with better outcomes and anti-PD-1 response in NSCLC patients.
Conclusions:
- CD4+ TRMs play a significant role in anti-tumor immunity in NSCLC.
- JAML is a key mediator of CD4+ TRM function and dendritic cell recruitment.
- Targeting CD4+ TRMs and JAML offers a promising strategy to improve anti-PD-1 immunotherapy efficacy in NSCLC.
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