TIME Is Ticking for Cervical Cancer

Abstract

Cervical cancer (CC) is a major health problem among reproductive-age females and comprises a leading cause of cancer-related deaths. Human papillomavirus (HPV) is the major risk factor associated with CC incidence. However, lifestyle is also a critical factor in CC pathogenesis. Despite HPV vaccination introduction, the incidence of CC is increasing worldwide. Therefore, it becomes critical to understand the CC tumor immune microenvironment (TIME) to develop immune cell-based vaccination and immunotherapeutic approaches. The current article discusses the immune environment in the normal cervix of adult females and its role in HPV infection. The subsequent sections discuss the alteration of different immune cells comprising CC TIME and their targeting as future therapeutic approaches.

Keywords: HPV; TIME; cervical cancer; cervix; immune cells; inflammation.

Figure 1

Schematic representation of the immune-cell population in the normal adult cervix and CC TIME. (A) Immune-cell population in the normal adult human cervix. The cervix is divided into ecto- and endocervix. Endocervix is rich in mucus and glandular goblet cells. Endocervix opens in the uterus. The zone connecting the endo- and ectocervix is called the transformation zone (TZ). Ectocervix is rich in innate immune cell population (Keratinocytes, LC, DC, macrophages, and NK cells) due to its increased chances of exposure to potential pathogens. However, the T-cell population does not vary in the endo- and ectocervix. (B). Immune-cell population in the CC TIME. CC TIME supporting tumor growth and metastasis becomes immunosuppressive and TANs, TAMs (M2 macrophages), MDSCs, tDCs, and T_regs predominate it. On the other antitumor Th1 and cytotoxic CD8⁺ T and NK cells decrease in number. Details are mentioned in the text.

Figure 2

HR-HPV-mediated CC immunopathogenesis. HR-HPVs infect basal epithelial cells, keratinocytes, and fibroblasts. HR-HPV infection transforms epithelial cells into neoplastic cells and later into cancer. The other keratinocytes escape from tumorigenic transformation and undergo apoptosis to support the immunosuppressive environment for tumor growth. In epithelial cells, HR-HPV infection prevents their apoptosis by inducing p53 mutation that also inhibits the cGAS/STING-mediated antitumor immune response. In addition, other proinflammatory innate immune functions of epithelial cells are also blocked, creating a chronic tumor-supportive immunosuppressive niche. Notably, in keratinocytes, only cGAS/STING-mediated NF-κB-mediated release of proinflammatory cytokines is inhibited leaving the type 1 IFN generation intact. This leads to the chronic type 1 IFN generation, which supports tumor growth. Furthermore, HR-HPV escapes phagocytosis by antigen-presenting cells (APCs, macrophages, LCs, and DCs) and antigen presentation to T and B cells. Metabolites released in the TIME by cancer cells further suppress cDC1s and NK cells. For example, DCs repolarize to tDCs in the presence of tryptophan and its metabolism by IDO. Details are discussed in the text.

Figure 3

Cervical cancer and Immune cells crosstalk to create and support the immunosuppressive CC TIME. Cancerous CECs with increased aerobic glycolysis (due to increased energy demand to maintain their rapid growth and proliferation) overproduce lactate. This lactate is released into the TME or TIME to create an acidic microenvironment. The acidic TME induces apoptotic cell death of different antitumor immune cells and reprograms their immunometabolism to polarize them to tumor-supportive immunosuppressive immune cells (M1 to M2 macrophages, increase in MDSCs, TANs, T_regs, and tDCs). These immunosuppressive immune cells synthesize, express, and release different tumor-promoting immunosuppressive molecules for their growth and proliferation along with supporting the cancer growth, proliferation, and metastasis. These immune cells also release angiogenic factors to support neoangiogenesis for cancer survival and metastasis. Eosinophils and mast cells release several factors (TSLP, TNF-α, histamine, and catecholamines) to support immunosuppressive CC TIME and cancer-cell proliferation and metastasis. Details are mentioned in the text.