The immunological heterogeneity of squamous cell carcinoma and adenocarcinoma of the uterine cervix: a systematic review

Abstract

Background: Cervical cancer is the fourth most common malignancy in women worldwide and generally driven by persistent infection with high-risk human papillomavirus. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the two most common histological subtypes, with a relative increase in adenocarcinomas in the last decades. The immunological differences between cervical squamous cell carcinoma and adenocarcinoma remain largely unexplored. Understanding these distinctions is crucial for developing tailored therapies that can improve treatment outcomes for patients with cervical cancer. This systematic review provides an overview of the immunological features of squamous cell carcinoma and adenocarcinoma of the uterine cervix.

Methods: A systematic search was performed in PubMed, Embase.com, Web of Science, and Cochrane Library. All articles addressing immunological features of squamous cell carcinoma and adenocarcinoma of the uterine cervix were reviewed and included based on predefined inclusion and exclusion criteria.

Results: In total, 3207 articles were screened, of which 43 were included. Studies show that cervical squamous cell carcinomas are characterised by a more inflamed tumour microenvironment, but also contain more regulatory T cells and immune checkpoints. In contrast, adenocarcinomas are characterised by lower immune cell infiltration, contributing to its poorer prognosis and more limited response to treatment.

Conclusion: The observed differences emphasize the need for further research into subtype-specific differences and distinct therapeutic strategies. For squamous cell carcinomas, future research should focus on combinatorial immune checkpoint blockade, including regulatory T cell-depleting strategies. For adenocarcinomas, oncolytic virotherapy, therapeutic vaccination, and oncogenic signalling interference should be explored.

Keywords: Adenocarcinoma; Cervical cancer; Human papillomavirus; Immunotherapy; Squamous cell carcinoma; Tumour microenvironment.

Fig. 1

PRISMA 2020 flow diagram of the search and selection process. Abbreviations:AC; adenocarcinoma, SCC; squamous cell carcinoma.

Fig. 2

Schematic overview of the different immune characteristics of SCC and AC of the cervix. SCC shows enhanced immune cell infiltration, with more TILs and pro-inflammatory (M1-like) macrophages, whereas AC shows more macrophages polarised towards an immunosuppressive (M2-like) phenotype. SCC is characterised by more immunosuppressive Tregs, possibly restraining effector T cells. SCC tumours exhibit increased expression of immune checkpoints (indicated in the figure as PD-L1, PD-1, and CTLA-4), suggesting tumour immune evasion and T cell exhaustion. cDC1 are more abundant in SCC, which attract effector T cells and are associated with response to immune checkpoint blockade. LCs, indicative of improved prognosis, infiltrate tumour nests in SCC but reside in the surrounding stroma of AC. The levels of CXCL 9, CXCL10, and CXCL11, are higher in SCC, indicative of enhanced T cell recruitment as compared to AC where it is consistent with a less T cell inflamed tumour microenvironment. The expression of IFN-γ, associated with antitumor immunity, was found to be higher in SCC compared to AC, as were the levels of IL-10 and TGFβ. The inflamed microenvironment in SCC likely supports effective T cell mediated antitumor immunity and may explain higher checkpoint blockade efficacy compared to AC. The expression of multiple immune checkpoints and high Treg rates in SCC support the validity of exploring checkpoint blockade combinations and Treg-depleting strategies, such as blockade of PD-1 and CTLA-4. The immune excluded and immune deserted immunotype in AC may require immunotherapeutic strategies to prime and recruit antitumor T cells, such as therapeutic vaccines, oncolytic viruses or modulation of oncogenic signalling pathways. Abbreviations: AC; adenocarcinoma. cDC1; conventional type 1 dendritic cells. CXCL; chemokine (C-X-C motif) ligands. Cytotoxic T-Lymphocyte Associated protein-4. EM; effector memory. IFN-γ; interferon-gamma. IL-10; interleukin-10. LC; Langerhans cells. PD-1; programmed death-1. PD-L1; programmed death ligand-1. SCC; squamous cell carcinoma. TGFβ; transforming growth factor beta. TILs; tumour-infiltrating lymphocytes. Tregs; regulatory T cells.