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Immunosuppression in Ovarian Cancer and the Path to Successful Immunotherapy

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 14885

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Special Issue Editor

Prof. Dr. An Coosemans

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Guest Editor

Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, O&N1 box 603, Herestraat 49, 3000 Leuven, Belgium
Interests: ovarian cancer; uterine sarcoma; glioblastoma; immunotherapy; MDSC; immunosuppression

Special Issue Information

Ovarian cancer has the fifth highest mortality rate among women diagnosed with cancer in Europe. Ovarian cancer is a silent killer, metastasizing throughout the abdomen before causing any symptoms. Consequently, 63% of patients are detected at FIGO stage III or IV, leading to an overall 5-year survival of only 20%. The introduction of maximal cytoreductive debulking surgery, Bevacizumab (anti-VEGF (vascular endothelial growth factor)) and PARP inhibitors (Poly (ADP-ribose) polymerase) have drastically improved survival, but with a relapse rate of still 80%, we face certain boundaries.

The immune system is now known to play a pivotal role in the onset and development of cancer. The adaptive and innate immune responses are mobilized to eliminate neoplastic cells as they emerge. In some cases, elimination is not entirely successful and an equilibrium phase is established, whereby neoplastic cells enter a dormant state, side by side with the immune system. During this process, tumor cells can be edited and consequently escape this immunological control. Eventually, the immune system fails and uncontrolled tumor proliferation occurs. Tumors themselves and/or through their interaction with the microenvironment may attract immunosuppressive cells, such as MDSC (myeloid derived suppressor cells), Treg (regulatory T cells), tumor promoting M2 macrophages, and others, to divert immune detection and facilitate unregulated tumor growth. Immunological evasion arises in all tumors, but the key players establishing the immune suppressive microenvironment are different per tumor, maybe even for different stages of the disease. Knowledge of the immune system in ovarian cancer is, so far, mainly limited to the intratumoral behavior of the adaptive immune system. The success rate of immune checkpoint inhibitor therapy in monotherapy is 10% for ovarian cancer. This is far below the success rate in, for example, melanoma (45% with Nivolumab). Because of the highly aggressive nature of ovarian cancer, this is hardly a surprise. Combinatorial strategies, combining immunotherapy with, for example, chemotherapy, are mandatory. However, the first results of these combinatorial trials have been disappointing as well. The JAVELIN Ovarian 100 and 200 trials were prematurely stopped because the primary endpoints (increase of survival) were not reached. In the JAVELIN Ovarian 100, the combinations had a reduced survival compared to chemotherapy alone (Figure 1). Additionally, in 2008, Alberts et al. published a study combining carboplatin-paclitaxel with interferon gamma 1 beta, which resulted in a decreased survival compared to chemotherapy alone.

Understanding and dealing with the specific immune biology of ovarian cancer is a mandatory key to successful immunotherapy. Therefore, we believe it is necessary to group all relevant information on this topic to increase the power of immunotherapeutic strategies in ovarian cancer.

Prof. Dr. An Coosemans
Guest Editor

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. Cancers 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 2900 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

immunosuppression
ovarian cancer
immunotherapy
MDSC
Treg
macrophages
neutrophils

Published Papers (5 papers)

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Research

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20 pages, 7750 KiB

Open AccessArticle

Release of Interferon-β (IFN-β) from Probiotic Limosilactobacillus reuteri-IFN-β (LR-IFN-β) Mitigates Gastrointestinal Acute Radiation Syndrome (GI-ARS) following Whole Abdominal Irradiation

by Diala F. Hamade, Michael W. Epperly, Renee Fisher, Wen Hou, Donna Shields, Jan-Peter van Pijkeren, Amitava Mukherjee, Jian Yu, Brian J. Leibowitz, Anda M. Vlad, Lan Coffman, Hong Wang, M. Saiful Huq, Ziyu Huang, Claude J. Rogers and Joel S. Greenberger

Cancers 2023, 15(6), 1670; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061670 - 08 Mar 2023

Cited by 1 | Viewed by 1611

Abstract

Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Thus, strategies to mitigate toxicity are important and can revitalize the current standard of care. We previously established that LR-IL-22 protects the intestine from WAI. We now hypothesize that LR-IFN-β is an effective radiation protector and mitigator and is rapidly cleared from the digestive tract, making it an option for intestinal radioprotection. We report that the gavage of LR-IFN-β during WAI provides improved intestinal barrier integrity and significantly preserves the numbers of Lgr5+GFP+ intestinal stem cells, improving survival. The rapid clearance of the genetically engineered probiotic from the digestive tract renders it a safe and feasible radiation mitigator. Therefore, the above genetically engineered probiotic is both a feasible and effective radiation mitigator that could potentially revolutionize the management of OC patients. Furthermore, the subsequent addition of platinum/taxane-based chemotherapy to the combination of WAI and LR-IFN-β should reduce tumor volume while protecting the intestine and should improve the overall survival in OC patients. Full article

(This article belongs to the Special Issue Immunosuppression in Ovarian Cancer and the Path to Successful Immunotherapy)

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13 pages, 1788 KiB

Open AccessArticle

Neo-Adjuvant Chemotherapy Reduces, and Surgery Increases Immunosuppression in First-Line Treatment for Ovarian Cancer

by Christine De Bruyn, Jolien Ceusters, Chiara Landolfo, Thaïs Baert, Gitte Thirion, Sandra Claes, Ann Vankerckhoven, Roxanne Wouters, Dominique Schols, Dirk Timmerman, Ignace Vergote and An Coosemans

Cancers 2021, 13(23), 5899; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235899 - 24 Nov 2021

Cited by 9 | Viewed by 1965

Abstract

In monotherapy, immunotherapy has a poor success rate in ovarian cancer. Upgrading to a successful combinatorial immunotherapy treatment implies knowledge of the immune changes that are induced by chemotherapy and surgery. Methodology: Patients with a new d ovarian cancer diagnosis underwent longitudinal blood samples at different time points during primary treatment. Results.: Ninety patients were included in the study (33% primary debulking surgery (PDS) with adjuvant chemotherapy (ACT), 61% neo-adjuvant chemotherapy (NACT) with interval debulking surgery (IDS), and 6% debulking surgery only). Reductions in immunosuppression were observed after NACT, but surgery reverted this effect. The immune-related proteins showed a pronounced decrease in immune stimulation and immunosuppression when primary treatment was completed. NACT with IDS leads to a transient amelioration of the immune microenvironment compared to PDS with ACT. Conclusion: The implementation of immunotherapy in the primary treatment schedule of ovarian cancer cannot be induced blindly. Carboplatin–paclitaxel seems to ameliorate the hostile immune microenvironment in ovarian cancer, which is less pronounced at the end of primary treatment. This prospective study during primary therapy for ovarian cancer that also looks at the evolution of immune-related proteins provides us with an insight into the temporary windows of opportunity in which to introduce immunotherapy during primary treatment. Full article

(This article belongs to the Special Issue Immunosuppression in Ovarian Cancer and the Path to Successful Immunotherapy)

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25 pages, 2937 KiB

Open AccessArticle

Murlentamab, a Low Fucosylated Anti-Müllerian Hormone Type II Receptor (AMHRII) Antibody, Exhibits Anti-Tumor Activity through Tumor-Associated Macrophage Reprogrammation and T Cell Activation

by Mélissa Prat, Marie Salon, Thibault Allain, Olivier Dubreuil, Grégory Noël, Laurence Preisser, Bérangère Jean, Lydie Cassard, Fanny Lemée, Isabelle Tabah-Fish, Bernard Pipy, Pascale Jeannin, Jean-François Prost, Jean-Marc Barret and Agnès Coste

Cancers 2021, 13(8), 1845; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081845 - 13 Apr 2021

Cited by 5 | Viewed by 3548

Abstract

AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and TAM-like macrophages to an M1-like phenotype characterized by a strong expression of co-stimulation markers, pro-inflammatory cytokines and chemokines, favoring T cell recruitment and activation. Moreover, we show that murlentamab treatment shifts CD4⁺ Th1/Th2 balance towards a Th1 response and activates CD8⁺ T cells. Altogether, these results suggest that murlentamab, through naïve macrophage orientation and TAM reprogrammation, stimulates the anti-tumor adaptive immune response. Those mechanisms might contribute to the sustained clinical benefit observed in advanced cancer patients treated with murlentamab. Finally, the enhanced murlentamab activity in combination with pembrolizumab opens new therapeutic perspectives. Full article

(This article belongs to the Special Issue Immunosuppression in Ovarian Cancer and the Path to Successful Immunotherapy)

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Review

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29 pages, 1441 KiB

Open AccessReview

Dendritic Cell Vaccines: A Promising Approach in the Fight against Ovarian Cancer

by Aarushi Audhut Caro, Sofie Deschoemaeker, Lize Allonsius, An Coosemans and Damya Laoui

Cancers 2022, 14(16), 4037; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14164037 - 21 Aug 2022

Cited by 12 | Viewed by 3458

Abstract

Ovarian cancer (OC) is the deadliest gynecological malignancy in developed countries and is the seventh-highest cause of death in women diagnosed with cancer worldwide. Currently, several therapies are in use against OC, including debulking surgery, chemotherapy, as well as targeted therapies. Even though the current standard-of-care therapies improve survival, a vast majority of OC patients relapse. Additionally, immunotherapies have only resulted in meager patient outcomes, potentially owing to the intricate immunosuppressive nexus within the tumor microenvironment. In this scenario, dendritic cell (DC) vaccination could serve as a potential addition to the therapeutic options available against OC. In this review, we provide an overview of current therapies in OC, focusing on immunotherapies. Next, we highlight the potential of using DC vaccines in OC by underscoring the different DC subsets and their functions in OC. Finally, we provide an overview of the advances and pitfalls of current DC vaccine strategies in OC while providing future perspectives that could improve patient outcomes. Full article

(This article belongs to the Special Issue Immunosuppression in Ovarian Cancer and the Path to Successful Immunotherapy)

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22 pages, 2016 KiB

Open AccessReview

Innate Lymphoid Cells: Role in Immune Regulation and Cancer

by Douglas C. Chung, Nicolas Jacquelot, Maryam Ghaedi, Kathrin Warner and Pamela S. Ohashi

Cancers 2022, 14(9), 2071; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092071 - 21 Apr 2022

Cited by 7 | Viewed by 3283

Abstract

Immune regulation is composed of a complex network of cellular and molecular pathways that regulate the immune system and prevent tissue damage. It is increasingly clear that innate lymphoid cells (ILCs) are also armed with immunosuppressive capacities similar to well-known immune regulatory cells (i.e., regulatory T cells). In cancer, immunoregulatory ILCs have been shown to inhibit anti-tumour immune response through various mechanisms including: (a) direct suppression of anti-tumour T cells or NK cells, (b) inhibiting T-cell priming, and (c) promoting other immunoregulatory cells. To provide a framework of understanding the role of immunosuppressive ILCs in the context of cancer, we first outline a brief history and challenges related to defining immunosuppressive ILCs. Furthermore, we focus on the mechanisms of ILCs in suppressing anti-tumour immunity and consequentially promoting tumour progression. Full article

(This article belongs to the Special Issue Immunosuppression in Ovarian Cancer and the Path to Successful Immunotherapy)

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