PD-L1 on Tumor-Derived Extracellular Vesicles Induces CD8+ T Cell Terminal Exhaustion and Mediates Anti-PD-1
Ruihua Fang1, Bixue Huang1, Yun Li1
1Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, P. R. China.
Abstract:
Head and neck squamous cell carcinoma (HNSCC) demonstrates suboptimal responses to current immune checkpoint inhibitors (ICIs), with objective response rates (ORRs) of merely 15-20%. The molecular mechanisms underlying these low ORRs remain incompletely defined. Here, two functionally distinct CD8⁺ T cell subsets are identified within the tumor microenvironment: precursor exhausted T (Texprog) cells and terminally exhausted T (Texterm) cells. Notably, although anti-PD-1 therapy reduced Texprog cell frequencies, it failed to reverse Texterm cells. Elevated Texterm cell infiltration correlated with advanced tumor-node-metastasis (TNM) staging and poor prognosis. Furthermore, non-responders exhibited significantly higher baseline Texterm proportions than responders before immunotherapy. Multivariate analysis established stromal Texterm cell density as both an independent prognostic factor and predictor of ICIs resistance. Mechanistically, Texterm cell infiltration strongly correlated with PD-L1 on tumor-derived extracellular vesicles (PD-L1+EVs). Most importantly, it is demonstrated that PD-L1+EVs drive Texterm cell differentiation by upregulating the basic leucine zipper transcription factor, ATF-like (BATF) in CD8⁺ T cells. Knocking out PD-L1 on EVs reduced Texterm cell infiltration and BATF expression. These findings elucidate an EV-mediated immune evasion axis and reveal actionable targets to overcome immunotherapy resistance.
Insights
Head and neck squamous cell carcinoma (HNSCC) shows poor response to immune checkpoint inhibitors (ICIs). Terminally exhausted T cells (Texterm) resist therapy, driven by PD-L1 on extracellular vesicles (EVs), highlighting a new target for immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) has limited response to immune checkpoint inhibitors (ICIs), with objective response rates (ORRs) of 15-20%.
- The molecular mechanisms behind these low ORRs in HNSCC are not fully understood.
- CD8+ T cell exhaustion is a key factor in tumor immune evasion.
Purpose of the Study:
- To investigate the distinct roles of CD8+ T cell subsets in HNSCC immunotherapy response.
- To elucidate the mechanisms underlying resistance to anti-PD-1 therapy in HNSCC.
- To identify novel therapeutic targets for improving ICI efficacy in HNSCC.
Main Methods:
- Identification and characterization of precursor exhausted T (Texprog) and terminally exhausted T (Texterm) cells in HNSCC tumors.
- Analysis of the correlation between Texterm cell infiltration, clinical parameters (TNM staging), and ICI response.
- Investigation of the role of PD-L1 on tumor-derived extracellular vesicles (PD-L1+EVs) in driving T cell exhaustion via the transcription factor BATF.
Main Results:
- Two distinct CD8+ T cell subsets, Texprog and Texterm, were identified in the HNSCC tumor microenvironment.
- Anti-PD-1 therapy reduced Texprog cells but not Texterm cells.
- Elevated Texterm cell infiltration correlated with advanced TNM staging, poor prognosis, and resistance to ICIs.
- Texterm cell density was an independent prognostic factor and predictor of ICI resistance.
- Texterm cell infiltration strongly correlated with PD-L1+EVs.
- PD-L1+EVs were shown to drive Texterm cell differentiation by upregulating BATF in CD8+ T cells.
- Knocking out PD-L1 on EVs decreased Texterm cell infiltration and BATF expression.
Conclusions:
- Terminally exhausted T cells (Texterm) are a key mechanism of immunotherapy resistance in HNSCC.
- PD-L1 on extracellular vesicles (EVs) drives Texterm cell differentiation and immune evasion.
- Targeting the PD-L1+EV-mediated axis presents a promising strategy to overcome ICI resistance in HNSCC.
More Related Videos
07:36Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
10:29Semi-automatic PD-L1 Characterization and Enumeration of Circulating Tumor Cells from Non-small Cell Lung Cancer Patients by Immunofluorescence
Published on: August 14, 2019
