Cytotoxic Lymphocyte-Related Gene Signature in Triple-Negative Breast Cancer

To curate the signature genes of cytotoxic lymphocytes (CLs) and explore the heterogeneity based on the CL-related (CLR) gene signature, we analyzed the gene expression of 592 patients with histologically diagnosed triple-negative breast cancer. Based on the 13-gene panel, CLR signatures were curated and associated with the stage of tumor size. Patients in the CLR-low group exhibited the worse overall survival (OS) (median OS, 75.23 months vs. 292.66 months, p < 0.0001) and were characterized by the upregulation of the NF-κB, Wnt, and p53 pathways, the positive regulation of angiogenesis, and a higher expression of immune checkpoints including CTLA4, LAG3, CD86, ICOS, ICOSLG, and TNFSF9. In cancer immunotherapy cohorts (GSE157284, GSE35640, IMvigor210), a higher CLR signature score was remarkably associated with greater tumor shrinkage and immune characteristics consisting of higher PD-L1 and neoantigen expression, as well as an inflamed tumor microenvironment. In the pan-cancer atlas, the CLR signature was notably associated with patient survival and revealed a profound heterogeneity across the malignancy types. In sum, the CLR signature is a promising indicator for immune characteristics, tumor shrinkage, and survival outcomes following cancer immunotherapy in addition to the prognostic heterogeneity in the pan-cancer atlas.