BCL2A1high CD8+ T Cells Are a Survival-Associated Predictor of Immune Checkpoint Blockade Response in Lung Adenocarcinoma

TL;DR

High BCL2A1 expression in CD8+ T cells predicts better survival and response to immune checkpoint therapy in lung adenocarcinoma patients.

Contribution

BCL2A1 in CD8+ T cells is identified as a novel survival-associated predictor of immune checkpoint blockade response in lung adenocarcinoma.

Findings

BCL2A1high CD8+ T cells show enhanced signaling and coordination in responders to immune checkpoint therapy.

A tri-marker model combining BCL2A1, PD-L1, and a 27-gene score outperforms existing predictors in ICB response.

BCL2A1 upregulation is specifically linked to improved survival in immune checkpoint blockade-treated patients.

Abstract

Background: Immune checkpoint blockade (ICB) has revolutionized lung adenocarcinoma (LUAD) therapy, yet predictive bio-markers remain suboptimal. We hypothesized that BCL2A1 expression in CD8+ T cells may reflect immune endurance and complement PD-L1 in predicting ICB response. Methods: Integrating bulk and single-cell RNA-seq across multiple LUAD cohorts, this study performed differential expression, survival, and pathway analyses in a discovery cohort (n = 60) and validated findings across five independent cohorts (n = 126). Results: Single-cell profiling identified BCL2A1 enrichment in tissue-resident memory and proliferating subsets that appeared preferentially expanded in responders; cell–cell communication analysis revealed that BCL2A1high CD8+ T cells exhibited significantly enhanced outgoing signaling capacity (p = 0.0278), with proliferating subsets serving as intra-CD8+ coordination hubs and MIF pathway interactions achieving the highest intensity among all axes examined. BCL2A1 was significantly upregulated in responders (FDR < 0.05) and associated with improved ICB survival (HR = 0.43, p < 0.05), but not in non-ICB settings, suggesting treatment-specific prognostic relevance. A tri-marker model integrating BCL2A1, PD-L1 (CD274), and a 27-gene HOT score demonstrated favorable predictive performance (AUC = 0.826 discovery; macro-AUC = 0.774 validation), outperforming PD-L1 alone (AUC = 0.706) and established signatures including TIDE, IPS, TIS, and IFNG. Cross-platform simulations suggested high reproducibility (ρ = 0.982–0.993). Conclusions: These findings suggest BCL2A1 may serve as a bio-marker of CD8+ T-cell survival and enhanced intercellular coordination, and its integration with PD-L1 and immune activation markers may yield a reproducible ICB response predictor, pending clinical validation.

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