Abstract / Summary
Tissue-resident memory T cells (Trm) are crucial local sentinels in cancer immunity; yet, their functional diversity and the role in non-small cell lung cancer (NSCLC) immune checkpoint blockade (ICB) therapy remain incompletely understood. In this study, we conducted an integrated multidimensional analysis, incorporating single-cell RNA and TCR sequencing, as well as large-scale omics data to elucidate the functions of CD8⁺ Trm subsets in NSCLC patients receiving anti-PD-1/PD-L1 therapy. The Trm subsets, Trm-CD103, Trm-ZNF683, and Trm-NR4A1, expressed high levels of tissue-residency markers ITGAE (CD103) and ITGA1 (CD49a), alongside their respective key transcriptional regulators ZNF683 (Hobit) or NR4A1 (Nur77), respectively, while sharing core functional features of cytotoxicity and tissue residency. Importantly, CD103⁺ Trm cells were significantly enriched in anti-PD-1/PD-L1 therapy responders and their abundance correlated with improved survival after treatment. Repertoire analysis revealed clonal expansion and TCR overlap between Trm and effector/memory CD8 + T-cell subsets, underscoring their differentiation origins and integrated role in the antitumor immune response. We further developed a core gene signature associated with Trm-CD103 cells that can predict anti-PD-1/PD-L1 therapy response and patient prognosis and found it to be associated with an immunologically active tumor microenvironment. Mechanistically, we identified the transcription factor RBPJ as a key driver of Trm proliferation through integrated single-cell analyses and cross-referencing of a previous knockout mouse experiment dataset, linking its expression to enhanced ICB efficacy. Together, our findings elucidate the multifaceted functions of Trm cells in NSCLC patients, establishing them as critical mediators of antitumor immunity and promising biomarkers and therapeutic targets for immunotherapy.