Origins of pleural effusion CD8+ T cells reveal tumoral immune microenvironment

The origin of CD8⁺ T cells in malignant pleural effusion and their link to the tumor immune microenvironment (TIME) is not fully understood. Here, we conducted a comprehensive single-cell analysis for both transcriptomes and T cell receptor (TCR) repertoires in matched lung primary tumors, pleural metastases, pleural effusion, and peripheral blood from patients with MPE. We observed a significant expansion of clonal CD8⁺ T cells with shared TCRs widely present in both primary tumors and pleural metastases. Based on tissue-specific TCR abundance data, we identified a group of intratumorally expanded CD8⁺ T (int-T8) cells and another group of circulating expanded CD8⁺ T (cir-T8) cells, in which the int-T8 cells were potentially interacting with tumor cells (e.g., via Galectin-Tim3 pathway), and showed higher levels of tumor related markers (e.g., PDCD1, ITGAE, and ENTPD1). Moreover, we discovered that CD8⁺ T cells in pleural effusion originated primarily from two immediate sources, pleural metastases and circulating blood. Specifically, the CD103⁺CD8⁺ T cells in effusion predominantly came from pleural int-T8 cells, and their abundance in effusion correlated with the TIME and clinical response to immune checkpoint blockade therapies. Our findings shed light on the origins of CD8⁺ T cells in MPE and suggested its potential applications in personalized immunotherapy.