CD103 ^⁺ CD8 ^⁺ T cells in malignant pleural effusion as a clinically applicable biomarker for immunotherapy response in advanced lung cancer.

Abstract

e20535 Background: Malignant pleural effusion (MPE) in advanced lung cancer is associated with poor outcomes and limited benefit from immune checkpoint blockade (ICB). A practical biomarker from an easily accessible source is needed to guide treatment. CD103 identifies tissue-resident memory CD8⁺ T cells (Trm), which are pivotal in antitumor immunity, but their predictive value in MPE has not been established. Methods: Single-cell RNA and T-cell receptor (TCR) sequencing were performed on matched primary tumors, pleural metastases, MPE, and blood from 7 patients. Intratumorally expanded CD8⁺ T cells (int-T8) were characterized. CD103⁺CD8⁺ T cells in MPE were quantified by flow cytometry in an expanded cohort (N=35) and correlated with mutational status. Their association with ICB response was validated in an independent retrospective cohort (N=23) using multiplex immunohistochemistry and survival analysis. Results: Intratumorally expanded CD8⁺ T cells displayed a Trm phenotype (CD103⁺, PD-1⁺, CD39⁺). TCR analysis confirmed that CD103⁺CD8⁺ T cells in MPE were clonally derived from these tumor-specific Trm. The proportion of CD103⁺CD8⁺ T cells in MPE strongly correlated with intratumoral Trm abundance (R=0.86, P=0.0013). This cell population was enriched in KRAS-mutant compared to other mutant MPEs (such as EGFR-19dels). In the validation cohort, a high proportion of CD103⁺CD8⁺ T cells in MPE was associated with a significantly better objective response rate (90.9% vs. 16.7%) and longer median progression-free survival (206 vs. 70 days; HR, 0.22; 95% CI, 0.07 to 0.67; P < 0.0001). Notably, this 90.9% response rate stands in sharp contrast to the generally modest response rates (<30%) observed with ICB in unselected advanced lung cancer populations. Conclusions: CD103⁺CD8⁺ T cells in MPE constitute a tumor-specific Trm population that reflects the intratumoral immune microenvironment. This finding establishes a new, readily implementable biomarker assay from a routinely obtained liquid sample (thoracentesis). Measurement of this subset represents a clinically feasible approach that can help identify patients with advanced lung cancer most likely to benefit from immunotherapy.