Abstract Rationale Malignant pleural effusion (MPE) is a common manifestation of advanced lung cancer and is often associated with poor outcomes and limited response to immune checkpoint blockade (ICB). Identifying reliable biomarkers to predict ICB efficacy in patients with MPE remains an unmet clinical need. CD103, a marker of tissue-resident memory T cells (Trm), is closely linked to tumor-specific CD8+ T-cell immunity, but its predictive and translational value in MPE has not been established. Methods We conducted single-cell transcriptomic and T cell receptor (TCR) repertoire analyses on matched samples of primary lung tumors, pleural metastases, pleural effusions, and peripheral blood from patients with lung cancer-associated MPE. Intratumorally expanded CD8+ T (int-T8) cells were identified and characterized. Flow cytometry and multiplex immunohistochemistry were performed to quantify CD103+CD8+ T cells in pleural effusions and to examine their correlation with intratumoral T-cell subsets and clinical outcomes. The association between effusion CD103+CD8+ T-cell abundance and response to ICB was analyzed in a retrospective validation cohort. Results We identified a distinct subset of intratumorally expanded CD8+ T (int-T8) cells expressing PDCD1, ITGAE (CD103), and ENTPD1, displaying tumor-specific and tissue-resident features. TCR tracking demonstrated that CD103+CD8+ T cells in MPE predominantly originated from these int-T8 cells in pleural metastases. The proportion of CD103+CD8+ T cells in effusions strongly correlated with the abundance of int-T8 cells in tumors (R = 0.86, P = 0.0013). Clinically, patients with a high proportion of CD103+CD8+ T cells exhibited higher ICB response rates (90.9% vs. 16.7%, P = 0.0697) and significantly longer median progression-free survival (206 vs. 70 days, P 0.0001; hazard ratio 0.22, 95% CI 0.07-0.67). Conclusion CD103+CD8+ T cells in MPE represent tumor-specific, tissue-resident T cells reflecting the tumor immune microenvironment. Quantifying CD103+CD8+ T cells in pleural effusion provides a non-invasive, clinically practical biomarker for predicting ICB efficacy and supports precision immunotherapy decision-making in patients with advanced lung cancer. This abstract is funded by: None
He et al. (Fri,) studied this question.