Comprehensive landscape of the GZM gene family in pan-cancer: Based on large-scale omics research and single-cell sequencing validation

Abstract

Abstract The granzyme family plays a crucial role in the immune response against tumor cells. It is involved in inflammation, tumor development, and various survival pathways. However, the precise function of the GZM gene family in a wide range of cancers remains unclear. Through an analysis of cancer genome mapping data, we observed differential expression of the GZM gene family in tumors, which was associated with somatic copy number changes (SCNA) and DNA methylation. Notably, we found a strong positive correlation between the GZM gene family and PD-1 expression in various cancers, suggesting its involvement in tumor immune evasion. To elucidate the function of this gene family, we developed GZMscores, which showed significant differences between tumor and normal tissues across different cancers, and were also correlated with prognosis and clinical features. Pathway analysis revealed close associations between GZMscores and multiple immune and inflammatory pathways. High GZMscores were predictive of poor prognosis in diverse tumors. Our study provides a comprehensive analysis of the GZM gene family and underscores the potential of GZMscores-based cancer immunotherapy. Furthermore, our single-cell pan-carcinoma analysis demonstrated the close relationship between the GZM gene family and pDC_LILRA4 cells and cDC1_CLEC9A cells, suggesting their influence on tumor immunity and recruitment of effector T cells through the modulation of inflammatory factor release from pDC_LILRA4 cells. In TNBC single-cell analysis, we observed widespread expression of the GZM gene family in T cells and NK cells, and a strong correlation with CD8_MAIT-KLRB1, CD8-CXCL13, Bfoc-MKI67, Bmem-MKI67, cDC2-CD207, pDC-LILRA4, ILC1-CD160, ILC1-CX3CR1, ILC1-IFNG, and ILC1-IL32. In summary, our extensive multiomics and single-cell analysis shed light on the function and characteristics of the GZM gene family in different types of cancer. These findings emphasize the potential of harnessing the GZM gene family for patient immunotherapy responses and offer new directions for future immunotherapy. Additionally, our findings present a promising avenue for immunotargeted therapy in triple-negative breast cancer.