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Immunotherapy in Cervical and Vulvar Cancer
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Immunotherapy in Cervical and Vulvar Cancer

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Obstetrics & Gynecology".

Deadline for manuscript submissions: closed (20 January 2022) | Viewed by 17688

Special Issue Editors

Prof. Dr. Gemma G. Kenter

E-Mail Website
Guest Editor
Center Gynaecological Oncology Amsterdam, AmsterdamUMC and Netherlands Cancer Institute, Amsterdam, The Netherlands
Interests: treatment of cervical cancer; HPV; immunotherapy
Dr. Ekaterina S. Jordanova

E-Mail Website
Co-Guest Editor
Center for Gynecological Oncology Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Interests: HPV; cervical cancer; immunotherapy; checkpoint inhibitors; biomarkers; clinical trials; multiparameter immunohistochemistry; pathology

Special Issue Information

Dear Colleagues,

Cancer of the cervix and vulva remain a relevant problem in spite of the existence of preventive HPV vaccination. Over 500,000 women worldwide are diagnosed with cervical cancer, and the incidence of vulvar cancer—although a rare disease—is increasing. In low-income countries where the incidence is the highest, preventive measures like screening and vaccination are especially lacking. In many cases, the women are young, of childbearing age, or have families with young children.
The current treatment options, comprising surgery or chemoradiation, both have detrimental effects on the quality of life.
The fact that cervical cancer as well as vulvar cancer are both HPV-related cancer types warrants the use and application of immunotherapy. Although immunotherapy has demonstrated promising results in other cancer types, like melanoma and lung cancer, the attention for cancer of the female genital tract is still poor, and number of clinical studies and trials is low.
Immunotherapy can be a useful addition to the current treatment options with minimal complications. Selection of those patients that can benefit from this type of treatment is important, and can be made based on results from studies on the tumor microenvironment.
The present Special Issue aims to highlight the current status of immunotherapy in cervical and vulvar cancer as well as the role of predictors in successful treatment. Increasing clinicians’ knowledge through the presentation and discussion of the latest advances has potential benefits for other HPV-related cancer types.

Prof. Dr. Gemma G. Kenter
Dr. Katja Jordanova
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cervical cancer
  • vulvar cancer
  • HPV
  • immunotherapy

Published Papers (4 papers)

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Review

26 pages, 378 KiB  
Review
A Review of the Effects of Cervical Cancer Standard Treatment on Immune Parameters in Peripheral Blood, Tumor Draining Lymph Nodes, and Local Tumor Microenvironment
by Iske F. van Luijk, Sharissa M. Smith, Maria C. Marte Ojeda, Arlene L. Oei, Gemma G. Kenter and Ekaterina S. Jordanova
J. Clin. Med. 2022, 11(9), 2277; https://doi.org/10.3390/jcm11092277 - 19 Apr 2022
Cited by 5 | Viewed by 3356
Abstract
Cervical cancer remains a public health concern despite all the efforts to implement vaccination and screening programs. Conventional treatment for locally advanced cervical cancer consists of surgery, radiotherapy (with concurrent brachytherapy), combined with chemotherapy, or hyperthermia. The response rate to combination approaches involving [...] Read more.
Cervical cancer remains a public health concern despite all the efforts to implement vaccination and screening programs. Conventional treatment for locally advanced cervical cancer consists of surgery, radiotherapy (with concurrent brachytherapy), combined with chemotherapy, or hyperthermia. The response rate to combination approaches involving immunomodulatory agents and conventional treatment modalities have been explored but remain dismal in patients with locally advanced disease. Studies exploring the immunological effects exerted by combination treatment modalities at the different levels of the immune system (peripheral blood (PB), tumor-draining lymph nodes (TDLN), and the local tumor microenvironment (TME)) are scarce. In this systemic review, we aim to define immunomodulatory and immunosuppressive effects induced by conventional treatment in cervical cancer patients to identify the optimal time point for immunotherapy administration. Radiotherapy (RT) and chemoradiation (CRT) induce an immunosuppressive state characterized by a long-lasting reduction in peripheral CD3, CD4, CD8 T cells and NK cells. At the TDLN level, CRT induced a reduction in Nrp1+Treg stability and number, naïve CD4 and CD8 T cell numbers, and an accompanying increase in IFNγ-producing CD4 helper T cells, CD8 T cells, and NK cells. Potentiation of the T-cell anti-tumor response was particularly observed in patients receiving low irradiation dosage. At the level of the TME, CRT induced a rebound effect characterized by a reduction of the T-cell anti-tumor response followed by stable radioresistant OX40 and FoxP3 Treg cell numbers. However, the effects induced by CRT were very heterogeneous across studies. Neoadjuvant chemotherapy (NACT) containing both paclitaxel and cisplatin induced a reduction in stromal FoxP3 Treg numbers and an increase in stromal and intratumoral CD8 T cells. Both CRT and NACT induced an increase in PD-L1 expression. Although there was no association between pre-treatment PD-L1 expression and treatment outcome, the data hint at an association with pro-inflammatory immune signatures, overall and disease-specific survival (OS, DSS). When considering NACT, we propose that posterior immunotherapy might further reduce immunosuppression and chemoresistance. This review points at differential effects induced by conventional treatment modalities at different immune compartments, thus, the compartmentalization of the immune responses as well as individual patient’s treatment plans should be carefully considered when designing immunotherapy treatment regimens. Full article
(This article belongs to the Special Issue Immunotherapy in Cervical and Vulvar Cancer)
21 pages, 787 KiB  
Review
Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy
by Caroline L. P. Muntinga, Peggy J. de Vos van Steenwijk, Ruud L. M. Bekkers and Edith M. G. van Esch
J. Clin. Med. 2022, 11(5), 1432; https://doi.org/10.3390/jcm11051432 - 5 Mar 2022
Cited by 8 | Viewed by 3217
Abstract
Cervical high-grade squamous intraepithelial lesions (cHSILs) develop as a result of a persistent high-risk human papilloma virus (hrHPV) infection. The natural course of cHSIL is hard to predict, depending on a multitude of viral, clinical, and immunological factors. Local immunity is pivotal in [...] Read more.
Cervical high-grade squamous intraepithelial lesions (cHSILs) develop as a result of a persistent high-risk human papilloma virus (hrHPV) infection. The natural course of cHSIL is hard to predict, depending on a multitude of viral, clinical, and immunological factors. Local immunity is pivotal in the pathogenesis, spontaneous regression, and progression of cervical dysplasia; however, the underlying mechanisms are unknown. The aim of this review is to outline the changes in the immune microenvironment in spontaneous regression, persistence, and responses to (immuno)therapy. In lesion persistence and progression, the immune microenvironment of cHSIL is characterized by a lack of intraepithelial CD3+, CD4+, and CD8+ T cell infiltrates and Langerhans cells compared to the normal epithelium and by an increased number of CD25+FoxP3+ regulatory T cells (Tregs) and CD163+ M2 macrophages. Spontaneous regression is characterized by low numbers of Tregs, more intraepithelial CD8+ T cells, and a high CD4+/CD25+ T cell ratio. A ‘hot’ immune microenvironment appears to be essential for spontaneous regression of cHSIL. Moreover, immunotherapy, such as imiquimod and therapeutic HPV vaccination, may enhance a preexisting pro-inflammatory immune environment contributing to lesion regression. The preexisting immune composition may reflect the potential for lesion regression, leading to a possible immune biomarker for immunotherapy in cHSILs. Full article
(This article belongs to the Special Issue Immunotherapy in Cervical and Vulvar Cancer)
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Figure 1

29 pages, 1246 KiB  
Review
Immunotherapeutic Approaches for the Treatment of HPV-Associated (Pre-)Cancer of the Cervix, Vulva and Penis
by Tynisha S. Rafael, Jossie Rotman, Oscar R. Brouwer, Henk G. van der Poel, Constantijne H. Mom, Gemma G. Kenter, Tanja D. de Gruijl and Ekaterina S. Jordanova
J. Clin. Med. 2022, 11(4), 1101; https://doi.org/10.3390/jcm11041101 - 19 Feb 2022
Cited by 11 | Viewed by 6617
Abstract
Human papillomavirus (HPV) infection drives tumorigenesis in almost all cervical cancers and a fraction of vulvar and penile cancers. Due to increasing incidence and low vaccination rates, many will still have to face HPV-related morbidity and mortality in the upcoming years. Current treatment [...] Read more.
Human papillomavirus (HPV) infection drives tumorigenesis in almost all cervical cancers and a fraction of vulvar and penile cancers. Due to increasing incidence and low vaccination rates, many will still have to face HPV-related morbidity and mortality in the upcoming years. Current treatment options (i.e., surgery and/or chemoradiation) for urogenital (pre-)malignancies can have profound psychosocial and psychosexual effects on patients. Moreover, in the setting of advanced disease, responses to current therapies remain poor and nondurable, highlighting the unmet need for novel therapies that prevent recurrent disease and improve clinical outcome. Immunotherapy can be a useful addition to the current therapeutic strategies in various settings of disease, offering relatively fewer adverse effects and potential improvement in survival. This review discusses immune evasion mechanisms accompanying HPV infection and HPV-related tumorigenesis and summarizes current immunotherapeutic approaches for the treatment of HPV-related (pre-)malignant lesions of the uterine cervix, vulva, and penis. Full article
(This article belongs to the Special Issue Immunotherapy in Cervical and Vulvar Cancer)
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Figure 1

14 pages, 304 KiB  
Review
The Role of Immunotherapy in the Treatment of Advanced Cervical Cancer: Current Status and Future Perspectives
by Robert J. Walsh and David S. P. Tan
J. Clin. Med. 2021, 10(19), 4523; https://doi.org/10.3390/jcm10194523 - 29 Sep 2021
Cited by 13 | Viewed by 3440
Abstract
Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although [...] Read more.
Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although the majority of patients do not benefit from their use. This review summarises current knowledge and use of immune checkpoint blockade in cervical cancer as well as discussing the challenges faced in their clinical application, namely, the role of biomarker-driven ICI use, potential mechanisms of resistance, strategies to overcome such resistance and additional immunotherapy options beyond ICI. Full article
(This article belongs to the Special Issue Immunotherapy in Cervical and Vulvar Cancer)
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