{
  "abstract": "Background Understanding resistance to anti-programmed cell death protein 1 (PD-1) therapy is critical for developing reversal strategies. Although ectonucleotidase CD39 (ENTPD1) (CD39) + cluster of differentiation 8 (CD8)+ T cells have been associated with antitumor responses, the naïve regional distribution of these cells and their dysregulated dynamics as determinants of response or resistance to anti-PD-1 monoclonal antibody (mAb) therapy remain poorly characterized.Methods We employed targeted biopsy techniques to characterize the spatial infiltration of CD39 +CD8+ T cells within the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). It was further performed independent NSCLC cohort, flow cytometry, multiplex immunohistochemistry, single-cell RNA sequencing and functional studies to investigate these cells in vitro and in vivo.Results Region-specific CD39 +CD8+ T cells located outside hypoxic zones initially served as potential biomarkers to predict response to anti-PD-1 therapy. However, hypoxia gradients within the TME were associated with regional depletion of these cells in NSCLC. Subsequently, anti-PD-1 mAb treatment further reduced intratumoral CD39+CD8+ T-cell levels, even in the context of improved oxygenation following tumor regression, suggesting a feedback mechanism modulating antitumor immunity. Multiple assays revealed that the absence of CD39 impaired functional restoration of CD8+ T cells on PD-1 blockade. This finding was corroborated by distinct transcriptional profiles, enhanced cytotoxic/effector signatures, and a more oligoclonal and expanded T-cell receptor (TCR) repertoire in CD39+CD8+ T cells across the CD8+ T-cell differentiation continuum.Conclusions These findings identify CD39 +CD8+ T cells as an important regulator of anti-PD-1 therapy, whereas initial hypoxia followed by anti-PD-1 treatment sequentially shapes tumor-regional localization of these cells, ultimately linking to suboptimal immunotherapeutic responses.",
  "authors": [
    {
      "affiliations": [
        "Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, China",
        "Department of Clinical Laboratory, The First Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China"
      ],
      "name": "Jiajuan Wu"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China",
        "Department of Pulmonary and Critical Care Medicine, Xuzhou Central Hospital, Xuzhou, China"
      ],
      "name": "Jiawei Zhai"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China",
        "Department of Pulmonary and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, China"
      ],
      "name": "Leilei Lv"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China"
      ],
      "name": "Yaoxin Zhang"
    },
    {
      "affiliations": [
        "Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, China"
      ],
      "name": "Yu Shen"
    },
    {
      "affiliations": [
        "Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, China"
      ],
      "name": "Qiuxia Qu"
    },
    {
      "affiliations": [
        "Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China"
      ],
      "name": "Cheng Chen"
    }
  ],
  "title": "Sequential involvement of hypoxia and anti-PD-1 treatment in shaping tumor-regional CD39+CD8+ T cells highlights immunotherapy-resistant features in NSCLC",
  "uid": "a34ed59a-99cd-5a1a-b72e-e8a21d41e81f"
}