Cellular heterogeneity and key subsets of tissue-resident memory T cells in cervical cancer

Abstract Tissue-resident memory T cells (TRMs) play a critical role in cancer immunity by offering quick and effective immune responses. However, the cellular heterogeneity of TRMs and their significance in cervical cancer (CC) remain unknown. In this study, we generated and analyzed single-cell RNA sequencing data from 12,945 TRMs ( ITGAE + CD3D + ) and 25,627 non-TRMs ( ITGAE − CD3D + ), derived from 11 CC tissues and 5 normal cervical tissues. We found that TRMs were more immunoreactive than non-TRMs, and TRMs in CC tissues were more activated than those in normal cervical tissues. Six CD8 + TRM subclusters and one CD4 + TRM subcluster were identified. Among them, CXCL13 + CD8 + TRMs were more abundant in CC tissues than in normal cervical tissues, had both cytotoxic and inhibitory features, and were enriched in pathways related to defense responses to the virus. Meanwhile, PLAC8 + CD8 + TRMs were less abundant in CC tissues than in normal cervical tissues but had highly cytotoxic features. The signature gene set scores of both cell subclusters were positively correlated with the overall survival and progression-free survival of patients with CC following radiotherapy. Of note, the association between HLA-E and NKG2A , either alone or in a complex with CD94 , was enriched in CXCL13 + CD8 + TRMs interacting with epithelial cells at CC tissues. The in-depth characterization of TRMs heterogeneity in the microenvironment of CC could have important implications for advancing treatment and improving the prognosis of patients with CC.