The immunopathology of cancer varies. Cancer types in which the main effectors are CD8
+T cells specific to anti-tumor antigens (i.e., neoantigens) can be divided into “T cell inflamed,” where anti-tumor T cells are aggregated before treatment, and “non-T cell inflamed,” where such aggregation is absent. In T cell inflamed cancer, cytokines such as interferon (IFN)-γ, which are secreted by tumor antigen-specific T cells that recognize cancer cells, induce cancer cells and surrounding macrophages to express PD-L1, thereby suppressing CD8
+T cells and cancer elimination [
7]. Such pathology is thought to be present in a percentage of cervical cancers that develop through human papilloma virus (HPV) infection, indicating that drugs that block this PD-1/PD-L1 pathway would be beneficial [
8].
Sustained infection by HPV is profoundly related to the carcinogenesis of cervical cancer. Researchers have conducted mechanistic analyses of the relationship between HPV status and PD-L1 expression in HPV-related solid tumors, primarily in head and neck squamous cell carcinoma (SCC) and cervical cancer. In HPV-related head and neck SCC, PD-L1 expression on the cell membrane and IFN-γ mRNA upregulation were observed. This result indicated that IFN-γ was secreted through initial HPV infection, and subsequently induced PD-L1 expression [
9]. Moreover, PD-L1 DNA methylation was negatively correlated with PD-L1 mRNA expression and was significantly associated with HPV infection in The Cancer Genome Atlas (TCGA) cohorts, indicating that PD-L1 DNA methylation is associated with transcriptional silencing and HPV infection in head and neck SCC [
10]. Several teams that examined whether HPV infection affects PD-L1 expression in cervical cancer found that being HPV-positive is positively correlated with increased PD-L1 expression [
11,
12].
PD-L1 is expressed on the surface of cervical cancer tumor cells, antigen presenting cells, and tumor-infiltrating lymphocytes (TILs), whereas most PD-1-positive cells have been identified as T cells in the stroma of cervical cancer. PD-1 expression in the tumor stroma in cervical cancer is observed in 60.82% (59/97) of patients, according to one study [
13], and in 46.97% (31/66) according to another study [
14]. Many researchers have also examined PD-L1 expression in cervical cancer tissue. PD-L1 expression is observed in 34.4–96% of cervical cancer tissues, but it is rarely observed in histologically normal cervical tissue [
15,
16]. An analysis by histology type reported that PD-L1 expression is observed in 80% of cervical SCC [
12]. According to the TCGA database, PD-L1 amplification or acquisition was observed in 22% (28/129) of patients with cervical SCC [
17]. Furthermore, PD-L1 can be expressed on TILs, and this plays a role in the anti-tumor response blockade. According to a study of cervical SCC samples, the PD-L1 expression rates in cancer cells and TILs were 59.1% and 47.0%, respectively [
14]. These data suggest that both PD-L1 and PD-1 are widely expressed in cervical cancer tumor cells and stroma, indicating they could be a treatment target of a PD-1/PD-L1 inhibitor. To date, several lines of evidence support the possibility of using specific biomarkers to identify early stage cervical cancer and, in this way, offer a better prognosis for the patients [
18,
19]. Some biomarkers were analyzed in the carcinoma in situ (CIS), microinvasive, and squamous cell carcinoma (SCC) of the uterine cervix. There was a highly significant increase in PDL1 expression and decrease in Ki-67 (each
p < 0.001) in microinvasive cancer compared to CIS, whereas p16 and E6/E7 remained stable. As the lesion progressed to SCC, p16 and E6/E7 RNA remained strongly overexpressed with a concomitant over expression of importin-β and Ki67 [
19]. These data suggest that PD-L1 may be a useful biomarker to differentiate CIS from microinvasive cancer and, thus, anti-PD-L1 therapy may inhibit the progression of CIS to the invasive stage.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is expressed on the T cell surface and, by binding to the B7 molecule expressed on the dendritic cells, it terminates T cell activity, thereby suppressing an excessive T cell immune response. CTLA-4 is constantly expressed on regulatory T cells (Tregs). As seen when analyzing the Treg frequency in tumors of cervical cancer, patients with high Treg frequency have significantly shorter OS than patients with low Treg frequency [
20], indicating that an anti-CTLA-4 antibody could be a treatment target.