Journal for immunotherapy of cancer · 2025
Cellular dynamics in cerebrospinal fluid unveils the key regulators of intracranial response to immune checkpoint inhibitors in NSCLC brain metastases.
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Li Yang-Si, Lai Wenpu, Yin Kai, Tu Hai-Yan, Li Liang, Lin Shou-Heng, Li Peng, Zhou De-Xiang, Guo Wei-Bang, Yang Jin-Ji, Zhou Qing, Zhong Wen-Zhao, Zhang Xu-Chao, Jiang Ben-Yuan, Wang Zhen, Yang Xue-Ning, Wang Bin-Chao, Pan Yi, Chen Hua-Jun, Xu Chong-Rui, Zeng Lu, Chen Zhi-Hong, Yan Hong-Hong, Sun Hao, Dong Zhong-Yi, Liu Si-Yang Maggie, Li Yangqiu, Luo Oscar Junhong, Zheng Mei-Mei, Wu Yi-Long
Аннотация
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.
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.