Abstract
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Background: Biomarkers associated with response to immune checkpoint blockade (ICB) in lung adenocarcinoma (LUAD) remain incompletely defined. This study examined the transcriptional landscape of BCL2A1 in CD8? T cells and evaluated its association with clinical outcomes in ICB-treated patients.
Results: Single-cell analysis revealed a distinct enrichment of BCL2A1 in tissue-resident memory and proliferating CD8+ T cell subsets, which appeared preferentially expanded in ICB responders. Cell-cell communication inference indicated that these BCL2A1-high CD8+ T cells possess high outgoing signaling potential (p = 0.0278), particularly involving the Macrophage Migration Inhibitory Factor (MIF) pathway. Clinically, high BCL2A1 expression was significantly associated with improved survival in ICB-treated patients (HR = 0.43, p < 0.05), an association not observed in non-ICB cohorts. Furthermore, we developed a "tri-marker" model combining BCL2A1, Programmed death-ligand 1 (PD-L1), and a 27-gene HOT score. This model demonstrated robust predictive performance (Discovery AUC = 0.826; Validation macro-AUC = 0.774), outperforming PD-L1 alone and established signatures such as Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenoscore (IPS), Tumor Inflammation Signature (TIS), and Interferon-Gamma (IFNG). Cross-platform simulations suggested high reproducibility (ρ = 0.982–0.993).
Conclusions: BCL2A1 marks a transcriptionally distinct subset of CD8? T cells associated with survival outcomes and inferred intercellular signaling activity in LUAD treated with ICB. Integration of BCL2A1 into a multi-marker framework may support improved stratification of patients receiving immunotherapy, warranting further prospective validation.
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