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24 pages, 4897 KiB

Open AccessArticle

Synergistic Combination of Luteolin and Asiatic Acid on Cervical Cancer In Vitro and In Vivo

by Ya-Hui Chen, Jyun-Xue Wu, Shun-Fa Yang and Yi-Hsuan Hsiao

Cancers 2023, 15(2), 548; https://doi.org/10.3390/cancers15020548 - 16 Jan 2023

Cited by 12 | Viewed by 2844

Abstract

Cervical cancer is an important issue globally because it is the second most common gynecological malignant tumor and conventional treatment effects have been shown to be limited. Lut and AsA are plant-derived natural flavonoid and triterpenoid products that have exhibited anticancer activities and [...] Read more.

Cervical cancer is an important issue globally because it is the second most common gynecological malignant tumor and conventional treatment effects have been shown to be limited. Lut and AsA are plant-derived natural flavonoid and triterpenoid products that have exhibited anticancer activities and can modulate various signaling pathways. Thus, the aim of the present study was to evaluate whether Lut combined with AsA could enhance the anticancer effect to inhibit cervical cancer cell proliferation and examine the underlying molecular mechanisms in vitro and in vivo. The results of a CCK-8 assay showed that Lut combined with AsA more effectively inhibited the proliferation of CaSki and HeLa cells than Lut or AsA treatment alone. Lut combined with AsA caused apoptosis induction and sub-G1-phase arrest in CaSki and HeLa cells, as confirmed by flow cytometry, mitoROS analysis, antioxidant activity measurement and western blot assay. In addition, Lut combined with AsA significantly inhibited the cell migration ability of CaSki and HeLa cells in a wound-healing assay. Furthermore, Lut combined with AsA induced apoptosis and inhibited migration through downregulated PI3K/AKT (PI3K, AKT and p70S6K), JNK/p38 MAPK and FAK (integrin β1, paxillin and FAK) signaling and upregulated ERK signaling. In an in vivo study, Lut combined with AsA markedly inhibited cervical cancer cell-derived xenograft tumor growth. Collectively, the present study showed that Lut combined with AsA may be used as an anticancer agent to improve the prognosis of cervical cancer. Indeed, with additional research to develop standardized dosages, Lut and AsA combination therapy could also be applied in clinical medicine. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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14 pages, 301 KiB

Open AccessArticle

Targeted Next Generation Sequencing for Human Papillomavirus Genotyping in Cervical Liquid-Based Cytology Samples

by Karoline Andersen, Kasper Holm, Mette Tranberg, Cecilie Lebech Pedersen, Sara Bønløkke, Torben Steiniche, Berit Andersen and Magnus Stougaard

Cancers 2022, 14(3), 652; https://doi.org/10.3390/cancers14030652 - 27 Jan 2022

Cited by 10 | Viewed by 3631

Abstract

At present, human papillomavirus (HPV) testing is replacing morphology-based cytology as the primary tool for cervical cancer screening in several countries. However, the HPV assays approved for screening lack detection for all but one of the possibly carcinogenic HPV types and do not [...] Read more.

At present, human papillomavirus (HPV) testing is replacing morphology-based cytology as the primary tool for cervical cancer screening in several countries. However, the HPV assays approved for screening lack detection for all but one of the possibly carcinogenic HPV types and do not genotype all included HPV types. This study demonstrates the use of a targeted HPV next generation sequencing (NGS) panel to detect and genotype all 25 carcinogenic, probably carcinogenic, and possibly carcinogenic HPV types as well as the low-risk types HPV6 and HPV11. The panel was validated using a cohort of 93 paired liquid-based cytology samples (general practitioner (GP)-collected cervical samples and cervico-vaginal self-samples (SS)). Overall, the targeted panel had a sensitivity (GP = 97.7%, SS = 92.1%) and specificity (GP = 98.0%, SS = 96.4%) similar to the commercial HPV assays, Cobas^® 4800 HPV DNA test (Roche) and CLART^® HPV4S assay (GENOMICA). Interestingly, of the samples that tested positive with the NGS panel, three (6.4%) of the GP-collected samples and four (9.1%) of the self-samples tested positive exclusively for HPV types only included in the NGS panel. Thus, targeted HPV sequencing has great potential to improve the HPV screening programs since, as shown here, it can identify additional HPV positive cases, cases with HPV integration, variants in the HPV genome, and which HPV type is dominant in multi-infected cases. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

18 pages, 1537 KiB

Open AccessArticle

A Gene Signature Identifying CIN3 Regression and Cervical Cancer Survival

by Mari K. Halle, Ane Cecilie Munk, Birgit Engesæter, Saleha Akbari, Astri Frafjord, Erling A. Hoivik, David Forsse, Kristine E. Fasmer, Kathrine Woie, Ingfrid S. Haldorsen, Bjørn I. Bertelsen, Emiel A. M. Janssen, Einar Gudslaugsson, Camilla Krakstad and Irene T. Øvestad

Cancers 2021, 13(22), 5737; https://doi.org/10.3390/cancers13225737 - 16 Nov 2021

Cited by 10 | Viewed by 3281

Abstract

The purpose of this study was to establish a gene signature that may predict CIN3 regression and that may aid in selecting patients who may safely refrain from conization. Oncomine mRNA data including 398 immune-related genes from 21 lesions with confirmed regression and [...] Read more.

The purpose of this study was to establish a gene signature that may predict CIN3 regression and that may aid in selecting patients who may safely refrain from conization. Oncomine mRNA data including 398 immune-related genes from 21 lesions with confirmed regression and 28 with persistent CIN3 were compared. L1000 mRNA data from a cervical cancer cohort was available for validation (n = 239). Transcriptomic analyses identified TDO2 (p = 0.004), CCL5 (p < 0.001), CCL3 (p = 0.04), CD38 (p = 0.02), and PRF1 (p = 0.005) as upregulated, and LCK downregulated (p = 0.01) in CIN3 regression as compared to persistent CIN3 lesions. From these, a gene signature predicting CIN3 regression with a sensitivity of 91% (AUC = 0.85) was established. Transcriptomic analyses revealed proliferation as significantly linked to persistent CIN3. Within the cancer cohort, high regression signature score associated with immune activation by Gene Set enrichment Analyses (GSEA) and immune cell infiltration by histopathological evaluation (p < 0.001). Low signature score was associated with poor survival (p = 0.007) and large tumors (p = 0.01). In conclusion, the proposed six-gene signature predicts CIN regression and favorable cervical cancer prognosis and points to common drivers in precursors and cervical cancer lesions. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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20 pages, 9729 KiB

Open AccessArticle

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

by Anja L. Herrmann, Bianca J. Kuhn, Angela Holzer, Jeroen Krijgsveld, Karin Hoppe-Seyler and Felix Hoppe-Seyler

Cancers 2021, 13(19), 4995; https://doi.org/10.3390/cancers13194995 - 5 Oct 2021

Cited by 5 | Viewed by 3057

Abstract

The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims [...] Read more.

The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims to gain insights into the determinants which govern the switch between senescence and apoptosis in cervical cancer cells. We performed proteome analyses, proliferation studies by live-cell imaging and colony formation assays, senescence and apoptosis assays, and combination treatments of CPX with inhibitors of oxidative phosphorylation (OXPHOS) or glycolysis. We found that CPX downregulates OXPHOS factors and facilitates the induction of apoptosis under limited glucose availability, an effect which is shared by classical OXPHOS inhibitors. Under increased glucose availability, however, CPX-induced apoptosis is prevented and senescence is induced, an activity which is not exerted by classical OXPHOS inhibitors, but by other iron chelators. Moreover, we show that the combination of CPX with glycolysis inhibitors blocks cervical cancer proliferation in a synergistic manner. Collectively, our results reveal that the phenotypic response of cervical cancer cells towards CPX is strongly dependent on glucose availability, link the pro-apoptotic and pro-senescent activities of CPX to its bifunctionality as an OXPHOS inhibitor and iron chelator, respectively, and provide a rationale for combining CPX with glycolysis inhibitors. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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15 pages, 1284 KiB

Open AccessArticle

Genomic Characterization and Therapeutic Targeting of HPV Undetected Cervical Carcinomas

by Fiona J. Ruiz, Aishwarya Sundaresan, Jin Zhang, Chandra S. Pedamallu, Mari K. Halle, Vinodh Srinivasasainagendra, Jianqing Zhang, Naoshad Muhammad, Jennifer Stanley, Stephanie Markovina, Hemant K. Tiwari, Perry W. Grigsby, Camilla Krakstad, Julie K. Schwarz and Akinyemi I. Ojesina

Cancers 2021, 13(18), 4551; https://doi.org/10.3390/cancers13184551 - 10 Sep 2021

Cited by 18 | Viewed by 4248

Abstract

Cervical cancer tumors with undetectable HPV (HPV^U) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPV^U tumors to date (HPV^U = 35, HPV⁺ = [...] Read more.

Cervical cancer tumors with undetectable HPV (HPV^U) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPV^U tumors to date (HPV^U = 35, HPV⁺ = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV⁺ and HPV^U tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPV^U cancer cell lines. Patients with HPV^U CC tumors had worse progression-free and overall survival outcomes compared to HPV⁺ patients. TP53, ARID1A, PTEN, ARID5B, CTNNB1, CTCF, and CCND1 were identified as significantly mutated genes (SMGs) enriched in HPV^U tumors, with converging functional roles in cell cycle progression. In vitro HPV^U, but not HPV⁺, cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPV^U status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPV^U CC patients. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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12 pages, 1955 KiB

Open AccessArticle

Expression of Retroelements in Cervical Cancer and Their Interplay with HPV Infection and Host Gene Expression

by Gislaine Curty, Albert N. Menezes, Ayslan C. Brant, Miguel de Mulder Rougvie, Miguel Ângelo M. Moreira and Marcelo A. Soares

Cancers 2021, 13(14), 3513; https://doi.org/10.3390/cancers13143513 - 14 Jul 2021

Cited by 9 | Viewed by 2626

Abstract

Retroelements are expressed in diverse types of cancer and are related to tumorigenesis and to cancer progression. We characterized the expression of retroelements in cervical cancer and explored their interplay with HPV infection and their association with expression of neighboring genes. Forty biopsies [...] Read more.

Retroelements are expressed in diverse types of cancer and are related to tumorigenesis and to cancer progression. We characterized the expression of retroelements in cervical cancer and explored their interplay with HPV infection and their association with expression of neighboring genes. Forty biopsies of invasive cervical carcinoma (squamous cell carcinomas and adenocarcinomas) with genotyped HPV were selected and analyzed for human endogenous retrovirus (HERV) and long interspersed nuclear element 1 (L1) expression through RNA-seq data. We found 8060 retroelements expressed in the samples and a negative correlation of DNA methyltransferase 1 expression with the two most expressed L1 elements. A total of 103 retroelements were found differentially expressed between tumor histological types and between HPV types, including several HERV families (HERV-K, HERV-H, HERV-E, HERV-I and HERV-L). The comparison between HPV mono- and co-infections showed the highest proportion of differentially expressed L1 elements. The location of retroelements affected neighboring gene expression, such as shown for the interleukin-20 gene family. Three HERVs and seven L1 were located close to this gene family and two L1 showed a positive association with IL20RB expression. This study describes the expression of retroelements in cervical cancer and shows their association with HPV status and host gene expression. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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13 pages, 2596 KiB

Open AccessArticle

Carbonic Anhydrase IX Promotes Human Cervical Cancer Cell Motility by Regulating PFKFB4 Expression

by Min-Chieh Hsin, Yi-Hsien Hsieh, Yi-Hsuan Hsiao, Pei-Ni Chen, Po-Hui Wang and Shun-Fa Yang

Cancers 2021, 13(5), 1174; https://doi.org/10.3390/cancers13051174 - 9 Mar 2021

Cited by 28 | Viewed by 3488

Abstract

Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. In this study, CAIX overexpression in SiHa cells increased cell migration and [...] Read more.

Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. In this study, CAIX overexpression in SiHa cells increased cell migration and epithelial-to-mesenchymal transition (EMT). Silencing CAIX in the Caski cell line decreased the motility of cells and EMT. Furthermore, the RNA-sequencing analysis identified a target gene, bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB4), which is influenced by CAIX overexpression and knockdown. A positive correlation was found between CAIX expression and PFKFB4 levels in the cervical cancer of the TCGA database. Mechanistically, CAIX overexpression activated the phosphorylation of extracellular signal-regulated kinases (ERKs) to induce EMT and promote cell migration. In clinical results, human cervical cancer patients with CAIX^high/PFKFB4^high expression in the late stage had higher rates of lymph node metastasis and the shortest survival time. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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Review

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27 pages, 1887 KiB

Open AccessReview

Herpes Simplex Virus, Human Papillomavirus, and Cervical Cancer: Overview, Relationship, and Treatment Implications

by Daniel G. Sausen, Oren Shechter, Elisa S. Gallo, Harel Dahari and Ronen Borenstein

Cancers 2023, 15(14), 3692; https://doi.org/10.3390/cancers15143692 - 20 Jul 2023

Cited by 5 | Viewed by 10057

Abstract

There is a significant body of research examining the role of human papillomavirus (HPV) in the pathogenesis of cervical cancer, with a particular emphasis on the oncogenic proteins E5, E6, and E7. What is less well explored, however, is the relationship between cervical [...] Read more.

There is a significant body of research examining the role of human papillomavirus (HPV) in the pathogenesis of cervical cancer, with a particular emphasis on the oncogenic proteins E5, E6, and E7. What is less well explored, however, is the relationship between cervical cancer and herpes simplex virus (HSV). To date, studies examining the role of HSV in cervical cancer pathogenesis have yielded mixed results. While several experiments have determined that HPV/HSV-2 coinfection results in a higher risk of developing cervical cancer, others have questioned the validity of this association. However, clarifying the potential role of HSV in the pathogenesis of cervical cancer may have significant implications for both the prevention and treatment of this disease. Should this relationship be clarified, treating and preventing HSV could open another avenue with which to prevent cervical cancer. The importance of this is highlighted by the fact that, despite the creation of an effective vaccine against HPV, cervical cancer still impacts 604,000 women and is responsible for 342,000 deaths annually. This review provides an overview of HSV and HPV infections and then delves into the possible links between HPV, HSV, and cervical cancer. It concludes with a summary of preventive measures against and recent treatment advances in cervical cancer. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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23 pages, 3796 KiB

Open AccessReview

Molecular Pathology of Human Papilloma Virus-Negative Cervical Cancers

by Hiroshi Yoshida, Kouya Shiraishi and Tomoyasu Kato

Cancers 2021, 13(24), 6351; https://doi.org/10.3390/cancers13246351 - 17 Dec 2021

Cited by 16 | Viewed by 7674

Abstract

Cervical cancer is the fourth most common cancer in women worldwide and is predominantly caused by infection with human papillomavirus (HPV). However, a small subset of cervical cancers tests negative for HPV, including true HPV-independent cancers and false-negative cases. True HPV-negative cancers appear [...] Read more.

Cervical cancer is the fourth most common cancer in women worldwide and is predominantly caused by infection with human papillomavirus (HPV). However, a small subset of cervical cancers tests negative for HPV, including true HPV-independent cancers and false-negative cases. True HPV-negative cancers appear to be more prevalent in certain pathological adenocarcinoma subtypes, such as gastric- and clear-cell-type adenocarcinomas. Moreover, HPV-negative cervical cancers have proven to be a biologically distinct tumor subset that follows a different pathogenetic pathway to HPV-associated cervical cancers. HPV-negative cervical cancers are often diagnosed at an advanced stage with a poor prognosis and are expected to persist in the post-HPV vaccination era; therefore, it is important to understand HPV-negative cancers. In this review, we provide a concise overview of the molecular pathology of HPV-negative cervical cancers, with a focus on their definitions, the potential causes of false-negative HPV tests, and the histology, genetic profiles, and pathogenesis of HPV-negative cancers. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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28 pages, 1726 KiB

Open AccessReview

Molecular Markers to Predict Prognosis and Treatment Response in Uterine Cervical Cancer

by Maximilian Fleischmann, Georgios Chatzikonstantinou, Emmanouil Fokas, Jörn Wichmann, Hans Christiansen, Klaus Strebhardt, Claus Rödel, Nikolaos Tselis and Franz Rödel

Cancers 2021, 13(22), 5748; https://doi.org/10.3390/cancers13225748 - 17 Nov 2021

Cited by 18 | Viewed by 5296

Abstract

Uterine cervical cancer is one of the leading causes of cancer-related mortality in women worldwide. Each year, over half a million new cases are estimated, resulting in more than 300,000 deaths. While less-invasive, fertility-preserving surgical procedures can be offered to women in early [...] Read more.

Uterine cervical cancer is one of the leading causes of cancer-related mortality in women worldwide. Each year, over half a million new cases are estimated, resulting in more than 300,000 deaths. While less-invasive, fertility-preserving surgical procedures can be offered to women in early stages, treatment for locally advanced disease may include radical hysterectomy, primary chemoradiotherapy (CRT) or a combination of these modalities. Concurrent platinum-based chemoradiotherapy regimens remain the first-line treatments for locally advanced cervical cancer. Despite achievements such as the introduction of angiogenesis inhibitors, and more recently immunotherapies, the overall survival of women with persistent, recurrent or metastatic disease has not been extended significantly in the last decades. Furthermore, a broad spectrum of molecular markers to predict therapy response and survival and to identify patients with high- and low-risk constellations is missing. Implementation of these markers, however, may help to further improve treatment and to develop new targeted therapies. This review aims to provide comprehensive insights into the complex mechanisms of cervical cancer pathogenesis within the context of molecular markers for predicting treatment response and prognosis. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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20 pages, 1555 KiB

Open AccessReview

Genomic Risk Factors for Cervical Cancer

by Dhanya Ramachandran and Thilo Dörk

Cancers 2021, 13(20), 5137; https://doi.org/10.3390/cancers13205137 - 13 Oct 2021

Cited by 28 | Viewed by 13090

Abstract

Cervical cancer is the fourth common cancer amongst women worldwide. Infection by high-risk human papilloma virus is necessary in most cases, but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability in the range of other gynaecological cancers, only few [...] Read more.

Cervical cancer is the fourth common cancer amongst women worldwide. Infection by high-risk human papilloma virus is necessary in most cases, but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability in the range of other gynaecological cancers, only few genomic susceptibility loci have been identified thus far. Various case-control association studies have found corroborative evidence for several independent risk variants at the 6p21.3 locus (HLA), while many reports of associations with variants outside the HLA region remain to be validated in other cohorts. Here, we review cervical cancer susceptibility variants arising from recent genome-wide association studies and meta-analysis in large cohorts and propose 2q14 (PAX8), 17q12 (GSDMB), and 5p15.33 (CLPTM1L) as consistently replicated non-HLA cervical cancer susceptibility loci. We further discuss the available evidence for these loci, knowledge gaps, future perspectives, and the potential impact of these findings on precision medicine strategies to combat cervical cancer. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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15 pages, 743 KiB

Open AccessReview

Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

by Ya-Hui Chen, Po-Hui Wang, Pei-Ni Chen, Shun-Fa Yang and Yi-Hsuan Hsiao

Cancers 2021, 13(11), 2545; https://doi.org/10.3390/cancers13112545 - 22 May 2021

Cited by 18 | Viewed by 3710

Abstract

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug [...] Read more.

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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Other

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21 pages, 1241 KiB

Open AccessPerspective

Towards Novel Gene and Cell Therapy Approaches for Cervical Cancer

by Robert Polten, Ivana Kutle, Jens Hachenberg, Rüdiger Klapdor, Michael Morgan and Axel Schambach

Cancers 2023, 15(1), 263; https://doi.org/10.3390/cancers15010263 - 30 Dec 2022

Cited by 6 | Viewed by 2249

Abstract

Cervical cancer is one of the most common malignancies in women, and the majority of cases are caused by infection with high-risk human papilloma virus (HPV) subtypes. Despite effective preventative measures, such as vaccinations against HPV, over 300,000 women die world-wide from cervical [...] Read more.

Cervical cancer is one of the most common malignancies in women, and the majority of cases are caused by infection with high-risk human papilloma virus (HPV) subtypes. Despite effective preventative measures, such as vaccinations against HPV, over 300,000 women die world-wide from cervical cancer each year. Once cervical cancer is diagnosed, treatment may consist of radial hysterectomy, or chemotherapy and radiotherapy, or a combination of therapies dependent upon the disease stage. Unfortunately, overall prognosis for patients with metastatic or recurrent disease remains poor. In these cases, immunotherapies may be useful based on promising preclinical work, some of which has been successfully translated to the clinic. For example, approaches using monoclonal antibodies directed against surface proteins important for control of immune checkpoints (i.e., immune checkpoint inhibitors) were shown to improve outcome in many cancer settings, including cervical cancer. Additionally, initial clinical studies showed that application of cytotoxic immune cells modified to express chimeric antigen receptors (CAR) or T cell receptors (TCR) for better recognition and elimination of tumor cells may be useful to control cervical cancer. This review explores these important topics, including strengths and limitations of standard and developing approaches, and how some novel treatment strategies may be optimally used to offer the best possible treatment for cervical cancer patients. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cervical Cancer)

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