{
  "abstract": "Background Brain metastases (BrM) in non-small cell lung cancer (NSCLC) present a significant challenge due to poor prognosis. While immune checkpoint inhibitors (ICIs) have been standard treatments for NSCLC, their efficacy in BrM is variable, emphasizing the urgent need for predictive biomarkers and fundamental mechanisms.Methods Patients with NSCLC and BrM planning to receive ICI therapy were enrolled in the prospective cohort, dynamic cerebrospinal fluid (CSF) samples (n=20) were collected through lumbar puncture and used for single-cell RNA sequencing (scRNA-seq), and BrM tumors were collected if they have the indications of surgery, with integrating scRNA-seq data from external database (total n=20). Three independent cohorts underwent flow cytometry (n=8), proteomics analysis (n=31), and multiplex immunohistochemistry (n=25) for validation.Results Our study provided a high-resolution atlas of cellular dynamics in the CSF and BrM during ICI therapy in patients with NSCLC and BrM. Notably, we identified a key immune cell subset, CD4 +PDCD1+CXCR6+ T cells, as a positive predictor of ICI intracranial tumor responses, which presented highly functional and transcriptomic similarities in both CSF and BrM tumor environment. Moreover, CXCR6 could serve as a specific marker for CD4+PDCD1+ T cells linked to ICI response. Further, we revealed that the novel cluster of CD4+PDCD1+CXCR6+ T cells was closely associated with lymphocyte activation and aggregation in CSF and BrM of ICI responders, and classical dendritic cells of ICI responders interacted with CD4+PDCD1+CXCR6+ T cells for enhanced antigen presentation and inflammatory activation.Conclusion Our findings revealed critical insights into the immune landscape of NSCLC BrM under ICI therapy, highlighting CD4 +PDCD1+CXCR6+ T cells in CSF as a promising biomarker and illuminating fundamental mechanisms underlying ICI efficacy.",
  "authors": [
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Yang-Si Li"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital, School of Medicine, Jinan University, Guangzhou, China",
        "Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Wenpu Lai"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Kai Yin"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Hai-Yan Tu"
    },
    {
      "affiliations": [
        "Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Liang Li"
    },
    {
      "affiliations": [
        "China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China"
      ],
      "name": "Shou-Heng Lin"
    },
    {
      "affiliations": [
        "China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, GIBH-CUHK Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China"
      ],
      "name": "Peng Li"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "De-Xiang Zhou"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Wei-Bang Guo"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Jin-Ji Yang"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Qing Zhou"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Wen-Zhao Zhong"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Xu-Chao Zhang"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Ben-Yuan Jiang"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Zhen Wang"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Xue-Ning Yang"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Bin-Chao Wang"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Yi Pan"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Hua-Jun Chen"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Chong-Rui Xu"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Lu Zeng"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Zhi-Hong Chen"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Hong-Hong Yan"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Hao Sun"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China"
      ],
      "name": "Zhong-Yi Dong"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Chinese Thoracic Oncology Group (CTONG), Guangzhou, China"
      ],
      "name": "Si-Yang Maggie Liu"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital, School of Medicine, Jinan University, Guangzhou, China",
        "Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Yangqiu Li"
    },
    {
      "affiliations": [
        "Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China"
      ],
      "name": "Oscar Junhong Luo"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Mei-Mei Zheng"
    },
    {
      "affiliations": [
        "Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China"
      ],
      "name": "Yi-Long Wu"
    }
  ],
  "title": "Cellular dynamics in cerebrospinal fluid unveils the key regulators of intracranial response to immune checkpoint inhibitors in NSCLC brain metastases",
  "uid": "3893995e-bf54-5032-8c86-ed510e9f02de"
}