Abstract
OBJECTIVE: Deciphering the determinants of the intralesional immune reaction in cervical carcinogenesis may be conducive to improving the understanding of the disease and then improve outcomes. METHODS: Public gene-expression data and full clinical annotation were searched in Gene Expression Omnibus in the joint analysis of the array-based four eligible cohorts. The infiltrating estimation was quantified using microenvironment cell populations-counter algorithm and absolute-mode CIBERSORT and verified by flow cytometry analysis. An unsupervised classification on immune genes strongly associated with progression, designated by linear mixed-effects regression. We determined immune response and signaling features of the different developmental stages and immune phenotypes by functional annotation and systematically correlated the expression of immune checkpoints with cell-infiltrating characteristics. RESULTS: We identified the lesion-intrinsic immunosuppression mechanism was triggered at precancerous stages, such as genome instability and mutation, aerobic glycolysis, activation of proto-oncogene pathways and so forth. Predominant innate and adoptive cells were increasing from normalcy to cancer (B cell, total T cell, regulatory T cells [Tregs], monocytes, neutrophils, and M2-like macrophages) together with the decrease of CD4(+) T cell and CD8(+) T cell through the development of cervical cancer. Immune escape initiated on the expression of immunosuppressive molecules from high-grade squamous intraepithelial lesions (HSIL) and culminated in squamous cell carcinoma (SCC). Of note, the expression of immune checkpoints was escalated in the immune-hot and immune-warm phenotype largely encompassed by HSIL and SCC under the stress of both activated and suppressive immune responses. CONCLUSIONS: Immune surveillance is unleashing from low-grade squamous intraepithelial lesions onwards and immune-suppression mechanisms are triggered in HSIL. Thorough knowledge of the immune changing pattern during cervical tumorigenesis contributes to finding the potential therapeutic targets to susceptive patients towards immune checkpoints inhibitors.