Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women across the world. Cervical cancer is a major challenge for global health. The incidence and mortality vary widely with geographic location. Approximately 90% of cervical cancers occur in developing countries that lack organized screening and HPV vaccination. In lower human development index settings, cervical cancer ranks second in incidence and mortality. There are more than half a million new cervical cancer cases diagnosed and over 300 000 deaths worldwide each year. Cervical cancer represents a major public health problem even in developed countries such as United States. There were 13800 new cases and 4290 deaths estimated in 2020 in United States. Moreover, cervical cancer was the second leading cause of death in women aged 20–39 years in United States. Increasing incidence of cervical adenocarcinoma and attenuation of earlier declines for cervical squamous cell carcinoma emphasize the importance of the need for improved therapeutic options to reduce the burden of cervical cancer of the U.S.
Cervical cancer in early stage remains a curable disease that could be treated by surgical resection and concurrent chemoradiation. Women with bulky or locally advanced cervical cancer (IIB-IVA) when lesions are not amenable to high cure rates with surgery or radiation (RT) account for the majority of cervical cancer death. The most important risk factors affecting prognosis of cervical cancer are stage, status of the lymph nodes, tumor volume, depth of tumor invasion into the cervical stroma, and LVSI. The 5-year overall survival decreased significantly with rising stages, with FIGO stage IA, IB, IIB and IIIB were 90%, 83%, 70%, 42% respectively. A substantial percentage of advanced cervical cancer patients will undergo recurrence and poor prognosis[2, 20]. Recurrence rate of cervical cancer fluctuates from 10–74%. Tumor stage was one of the most pivotal factors related to recurrence. The recurrence rate by stage was as follows: 10% for stage IB, 17% for stage IIA, 23% for stage IIB, 42% for stage III and 74% for stage IVA. Prognosis of metastatic and recurrent cervical cancer was extremely poor with a median survival time of 12 months. Improved therapeutic options in management of cervical cancer, especially locally advanced cervical cancer is in urgent need.
High-risk subtypes of the human papilloma virus (HPV) are the cause of cervical cancer. Viral oncoproteins E6 and E7 leads to dysregulation of p53 and HIF-1 alpha, thus affecting cell cycle proteins and VEGF expression[24–27]. HPV is highly immunogenic and elicits immune responses in humans, thus immune might play important roles in carcinogenesis of cervical cancer. Incidence of cervical cancer was substantial declined in countries with high HPV vaccine coverage[28–30]. Immunotherapy fights against tumor cells through activating endogenous immune response which seems to switch on the new frontier of the anticancer treatment. Immunotherapy has different approaches, such as active immunotherapy (vaccine), passive immunotherapy (adoptive cellular transfer, antibodies and cytokines) and immunomodulation (cyclooxygenase 2 inhibitor). Discovery of immune checkpoint such as CTLA-4 and PD-1 plays an indispensable role in the development of cancer immunotherapy. It was surprising that immune checkpoint inhibitors anti-CTLA-4 and anti-PD-1 displayed enormous success in solid tumors. Similar to other solid tumors, novel immunotherapeutic approaches, such as immune checkpoint inhibitors have shown promising results in cervical cancer. Based on high response observed in KEYNOTE-158, the US Food and Drug Administration approved pembrolizumab inhibiting PD-1 for use in advanced cervical cancer with progressive disease either during or after chemotherapy.
Immunotherapy has shown encouraging results in cervical cancer treatment. Thus, implementing immunotherapeutic approaches earlier in advanced cervical cancer would seem to be most appropriate. However, the objective response rate with anti-PD-1/PD-L1 monotherapy is hovering at 20%. Moreover, immune-related toxicities and severe adverse effects can occur during PD-1/PD-L1 blockade therapy. PD-1/PD-L1 blockade therapy does not demonstrate efficacy in almost 80% cervical cancer patients, suggesting the potential mechanism of PD-1/PD-L1 in immunotherapy remain to be further clarified. So new immune checkpoint inhibitors or comprehensive understanding of specific mechanism underlying PD-1/PD-L1 regulation in carcinogenesis is in urgent need.
Immune infiltration of cervical cancer determines the immune activation of tumor microenvironment and is related with clinical outcome of patients. In this study, immunophenoscore of 28 infiltrated immune cell in TCGA cervical cancer was calculated. Univariate Cox regression analysis showed that activated B cell, activated CD8 T cell, eosinophil, monocyte, activated CD4 T cell, effector memory CD8 T cell, immature B cell, plasmacytoid dendritic cell were strongly associated with overall survival of cervical cancer. WGCNA revealed that magenta module was the most relevant module to immune infiltration. In total, we identified 10 kinds of infiltrated immune cells with strong correlation with magenta module. These were as follows: activated B cell (R = 0.88), activated CD8 T cell (R = 0.82), activated dendritic cell (R = 0.79), central memory CD4 T cell (R = 0.78), effector memory CD8 T cell (R = 0.85), immature B cell (R = 0.93), macrophage (R = 0.72), MDSC (R = 0.85), regulatory T cell (R = 0.71), T follicular helper cell (R = 0.72), type 1 T helper cell (R = 0.83).
By the use of WGCNA, we found magenta module showed the highest correlation with the immune infiltration of cervical cancer. The magenta module contained 609 immune-related genes. There were 153 genes picked up from the magenta module for further analysis after taking intersection of prognosis and immune infiltration. Through LASSO analysis, 15 immune-related genes (LAG3, CD74, CCL22, CH25H, OLR1, MIAT, BATF, IKZF3, TRARG, ACSL6, C11orf21, GTSF1, APOL1, CD1C, LINC00158) were included in prognostic classifier. Except CTLA-4 and PD-1/PD-L1 targeted cancer immunotherapy, LAG3 (lymphocyte activation gene-3, CD223) is the third inhibitory receptor to be targeted in the clinic. CD74 (invariant chain) plays a dispensable role in process of immune systems that it participates in antigen presentation, B-cell differentiation and inflammatory signaling. CD74 has the potential to be a therapeutic target in cancer and autoimmune disease. The chemokine CCL22 promoted regulatory T cell communication with dendritic cells to control immunity and was associated with poor prognosis[37, 38]. CH25H produces 25-hydroxycholesterol, which inhibited tumor-derived extracellular vesicles uptake and correlated with prognosis in melanoma patients. OLR1 (oxidized LDL receptor 1) was a possible link between obesity, dyslipidemia and cancer. OLR1 played carcinogenic role by activating NF-kB pathway to promote proliferation, migration and inhibit apoptosis and de novo lipogenesis. MIAT lncRNA was overexpressed in a number of malignancies and caused poor prognosis[41–43]. BATF was an important transcription factor regulating differentiation of early effector CD8 + T cells and was a prognostic indicator for patients with colon cancer. IKZF3 promoted growth of multiple tumors to cause poor prognosis.
The degree of immune infiltration significantly affected cervical cancer survival. In this study, the expression of 15 genes affected immune infiltration scores. Patients with higher immune scores had better prognosis. This study implied that prognosis value of risk score was associated with immune system. GSEA analysis showed that the 15-gene prognostic signature was obviously associated with PD-L1 expression and PD-1 checkpoint pathway in cancer. The prognostic signature could provide basis for potential immunotherapy in the future. However, the study has several limitations. First, no vitro or vivo molecular experiment was performed to verify our analysis, Second, our study was a retrospective study. So prospective study is in need to validate the findings of our study.