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14 pages, 2649 KiB

Open AccessArticle

Association of Genomic Instability Score, Tumor Mutational Burden, and Tumor-Infiltrating Lymphocytes as Biomarkers in Uterine Serous Carcinoma

by Elizabeth A. Bloom, Pamela N. Peters, Regina Whitaker, Shonagh Russell, Benjamin Albright, Shelly Cummings, Kirsten M. Timms, Thomas Slavin, Braden Probst, Kyle C. Strickland and Rebecca A. Previs

Cancers 2023, 15(2), 528; https://doi.org/10.3390/cancers15020528 - 15 Jan 2023

Cited by 1 | Viewed by 2579

Abstract

Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor [...] Read more.

Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in patients with USC. Methods: A retrospective cohort study evaluated patients with USC following staging surgery. The GIS and TMB were determined from archived specimens. We evaluated the tumoral expression of CD3, CD4, CD8, FOXP3, and CD68 using immunohistochemistry. T-tests were used to assess associations of TILs with the GIS. Results: We evaluated 53 patients with USC. The median GIS was 31 (range: 0–52) and a higher GIS was not associated with progression-free (PFS) or overall survival (OS). The median TMB was 1.35 mt/Mb; patients with TMB > 1.35 mt/Mb had improved PFS and OS (p = 0.005; p = 0.002, respectively). Tumors with increased CD3+ and CD4+ immune cells had a higher mean GIS (p = 0.013, p = 0.002). Conclusions: TMB > 1.35 mt/Mb was associated with improved survival in USC patients, whereas the GIS was not. Lower TMB thresholds may provide prognostic value for less immunogenic tumors such as USC. In this limited cohort, we observed that increased TIL populations were correlated with a higher GIS. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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19 pages, 1053 KiB

Open AccessArticle

Vulvar High-Grade Squamous Intraepithelial Lesions Treated with Imiquimod: Can Persistence of Human Papillomavirus Predict Recurrence?

by Maria-Eulalia Fernández-Montolí, Fatima Heydari, Fabrizia Lavecchia, Miquel-Ângel Pavón, Esther Guerra, Xavier Matias-Guiu, Maria-Dolores Marti and Sara Tous

Cancers 2022, 14(19), 4808; https://doi.org/10.3390/cancers14194808 - 30 Sep 2022

Cited by 4 | Viewed by 2437

Abstract

Objectives: Vulvar high-grade squamous intraepithelial lesion (vulvar HSIL) or vulvar intraepithelial neoplasia (VIN) is a premalignant condition that can progress to carcinoma. Imiquimod is a topical drug with high effectiveness and low morbidity. We aimed (1) to assess the long-term response to imiquimod [...] Read more.

Objectives: Vulvar high-grade squamous intraepithelial lesion (vulvar HSIL) or vulvar intraepithelial neoplasia (VIN) is a premalignant condition that can progress to carcinoma. Imiquimod is a topical drug with high effectiveness and low morbidity. We aimed (1) to assess the long-term response to imiquimod in a cohort of patients with vulvar HSIL and (2) and to analyze the role of HPV determined in pre- and post-imiquimod treatment biopsies in the persistence or recurrence of vulvar HSIL. Design: Retrospective study between 2011 and 2022. Setting: Referrals from the primary care area of Baix Llobregat treated in the gynecology department of a university hospital in Barcelona, Spain. Population: 20 women with vulvar HSIL treated with imiquimod. Methods: The inclusion criteria were vulvar HSIL, vulvar HPV determination by pre- and post-treatment biopsy, acceptance of medical treatment, at least one follow-up and 4 weeks of treatment. Main outcome measures: Histological diagnosis of vulvar HSIL with pre- and post-imiquimod HPV determination. Response to treatment (complete, partial, no response, recurrence). Results: After imiquimod, 10 (50%) and 6 (30%) cases had complete and partial responses, respectively. Another 4 cases (20%) did not respond. Before treatment, 19 (95%) cases were positive for vulvar HPV (16 cases had HPV type 16). After treatment, 10 cases (50%) were positive for HPV (8 cases with HPV type 16): 2 cases (20%) with a complete response, 5 cases (83.3%) with a partial response and 3 cases (75%) with no response. Eight of the 10 HPV-negative cases (80%) post-treatment showed a complete response. HPV type 16 was present in 16 cases (84.2%) pre-treatment and in 8 cases (80%) post-treatment. Ten patients underwent additional treatments following a partial response, no response or recurrence. The 2 HIV and 3 immunosuppressed patients treated with imiquimod showed a partial response and required additional treatment. All these patients were HPV-positive pre- and post-treatment (100%). Response to imiquimod was associated with post-treatment vulvar HPV positivity (p = 0.03). The median time to a complete response in HPV-negative cases was 4.7 months versus 11.5 months in HPV-positive cases post-imiquimod treatment. Recurrence of vulvar HSIL was observed in 7 patients (35%), with a median time to recurrence of 19.7 months (range 3.2–32.7). Recurrence was experienced in 10% of cases with a complete response, in 4/6 (66.6%) cases with a partial response, and in 2/4 (50%) women with no response. Four of the 7 recurrent cases (57%) were infected with HIV or immunosuppressed. Six (85%) of the recurrent cases were HPV-positive post-treatment (all were HPV type 16). Four (30.7%) of the non-recurrent cases were HPV-positive post-treatment with imiquimod (p = 0.05), two of which were HPV type 16 (50%). Conclusions: Imiquimod effectively treats vulvar HSIL. Cases with a complete response showed less HPV positivity post-treatment than partial or non-response cases. Recurrences were more frequent in those with a partial or no response to imiquimod, and in immunosuppressed patients. In recurrent cases, 85% were HPV-positive post-treatment, while 30.7% of non-recurrent cases were HPV-positive. HPV positivity in the post-treatment biopsy suggests the need for stricter follow-up of patients. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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18 pages, 1891 KiB

Open AccessArticle

Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer

by Shonagh Russell, Felicia Lim, Pamela N. Peters, Suzanne E. Wardell, Regina Whitaker, Ching-Yi Chang, Rebecca A. Previs and Donald P. McDonnell

Cancers 2022, 14(17), 4219; https://doi.org/10.3390/cancers14174219 - 30 Aug 2022

Cited by 1 | Viewed by 3487

Abstract

Despite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes in patients with ovarian cancer. Progress in this regard has been hindered by the lack of [...] Read more.

Despite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes in patients with ovarian cancer. Progress in this regard has been hindered by the lack of relevant syngeneic ovarian cancer models to study tumor immunity and evaluate immunotherapies. To address this problem, we developed a luciferase labeled murine model of high-grade serous ovarian cancer, STOSE.M1 luc. We defined its growth characteristics, immune cell repertoire, and response to anti PD-L1 immunotherapy. As with human ovarian cancer, we demonstrated that this model is poorly sensitive to immune checkpoint modulators. By developing the STOSE.M1 luc model, it will be possible to probe the mechanisms underlying resistance to immunotherapies and evaluate new therapeutic approaches to treat ovarian cancer. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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Review

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26 pages, 410 KiB

Open AccessReview

Tumor Immune Microenvironment in Gynecologic Cancers

by Daniel Margul, Camilla Yu and Mariam M. AlHilli

Cancers 2023, 15(15), 3849; https://doi.org/10.3390/cancers15153849 - 28 Jul 2023

Cited by 5 | Viewed by 2673

Abstract

Gynecologic cancers have varying response rates to immunotherapy due to the heterogeneity of each cancer’s molecular biology and features of the tumor immune microenvironment (TIME). This article reviews key features of the TIME and its role in the pathophysiology and treatment of ovarian, [...] Read more.

Gynecologic cancers have varying response rates to immunotherapy due to the heterogeneity of each cancer’s molecular biology and features of the tumor immune microenvironment (TIME). This article reviews key features of the TIME and its role in the pathophysiology and treatment of ovarian, endometrial, cervical, vulvar, and vaginal cancer. Knowledge of the role of the TIME in gynecologic cancers has been rapidly developing with a large body of preclinical studies demonstrating an intricate yet dichotomous role that the immune system plays in either supporting the growth of cancer or opposing it and facilitating effective treatment. Many targets and therapeutics have been identified including cytokines, antibodies, small molecules, vaccines, adoptive cell therapy, and bacterial-based therapies but most efforts in gynecologic cancers to utilize them have not been effective. However, with the development of immune checkpoint inhibitors, we have started to see the rapid and successful employment of therapeutics in cervical and endometrial cancer. There remain many challenges in utilizing the TIME, particularly in ovarian cancer, and further studies are needed to identify and validate efficacious therapeutics. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

30 pages, 2202 KiB

Open AccessReview

Immune Environment and Immunotherapy in Endometrial Carcinoma and Cervical Tumors

by Alexandra Lainé, Andrea M. Gonzalez-Lopez, Uzma Hasan, Ryotaro Ohkuma and Isabelle Ray-Coquard

Cancers 2023, 15(7), 2042; https://doi.org/10.3390/cancers15072042 - 29 Mar 2023

Cited by 8 | Viewed by 5335

Abstract

Endometrial cancer (EC) is the seventh most common tumor in women, and prognosis of recurrent and metastatic disease is poor. Cervical cancer (CC) represents the fifth most common gynecological cancer. While ECs are more common in developed countries, the incidence of CC has [...] Read more.

Endometrial cancer (EC) is the seventh most common tumor in women, and prognosis of recurrent and metastatic disease is poor. Cervical cancer (CC) represents the fifth most common gynecological cancer. While ECs are more common in developed countries, the incidence of CC has decreased due to the recent implementation of large screening and vaccination programs. Until very recently, patients with advanced or unresectable EC or CC had very limited treatment options and were receiving in first line setting platinum/taxane-based chemotherapy (CT). Significant progress in the treatment of gynecological cancers has occurred in the last few years, with the use of innovative targeted therapies and immunotherapy. However, targeting the immune system in patients with gynecological tumors remains challenging and is not always successful. In ovarian cancer, several immunotherapy treatment regimens have been investigated (as monotherapy and combination therapy in first and subsequent lines of treatment) and showed poor responses. Therefore, we specifically focused our review on EC and CC for their specific immune-related features and therapeutic results demonstrated with immunotherapy. We report recent and current immunotherapy-based clinical trials and provide a review of emerging data that are likely to impact immunotherapy development based on increased biomarkers’ identification to monitor response and overcome resistance. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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17 pages, 849 KiB

Open AccessReview

Molecular Characterizations of Gynecologic Carcinosarcomas: A Focus on the Immune Microenvironment

by Sanaa Nakad Borrego, Ernst Lengyel and Katherine C. Kurnit

Cancers 2022, 14(18), 4465; https://doi.org/10.3390/cancers14184465 - 14 Sep 2022

Cited by 5 | Viewed by 3197

Abstract

Gynecologic carcinosarcomas, specifically of endometrial and ovarian origin, are aggressive and rare tumors. Treatment data are limited and are often extrapolated from other histologies and smaller retrospective studies. While the optimal therapy approach remains contentious, treatment is often multimodal and may include surgery, [...] Read more.

Gynecologic carcinosarcomas, specifically of endometrial and ovarian origin, are aggressive and rare tumors. Treatment data are limited and are often extrapolated from other histologies and smaller retrospective studies. While the optimal therapy approach remains contentious, treatment is often multimodal and may include surgery, chemotherapy, radiation, or a combination of multiple strategies. However, despite aggressive treatment, these tumors fare worse than carcinomas of the same anatomic sites irrespective of their stage. Recent studies have described in-depth molecular characterizations of gynecologic carcinosarcomas. Although many molecular features mirror those seen in other uterine and ovarian epithelial tumors, the high prevalence of epithelial-mesenchymal transition is more unique. Recently, molecular descriptions have expanded to begin to characterize the tumor immune microenvironment. While the importance of the immune microenvironment has been well-established for other tumor types, it has been less systematically explored in gynecologic carcinosarcomas. Furthermore, the use of immunotherapy in patients with gynecologic carcinosarcomas has not been extensively evaluated. In this review, we summarize the available data surrounding gynecologic carcinosarcomas, with a focus on the immune microenvironment. We end with a discussion of potential immunotherapy uses and future directions for the field. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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24 pages, 732 KiB

Open AccessReview

Overview of Immune Checkpoint Inhibitors in Gynecological Cancer Treatment

by Boštjan Pirš, Erik Škof, Vladimir Smrkolj and Špela Smrkolj

Cancers 2022, 14(3), 631; https://doi.org/10.3390/cancers14030631 - 27 Jan 2022

Cited by 30 | Viewed by 7412

Abstract

In the last ten years, clinical oncology has been revolutionized by the introduction of oncological immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs) that transformed the standard of care of several advanced solid malignancies. Using ICIs for advanced gynecological cancers has [...] Read more.

In the last ten years, clinical oncology has been revolutionized by the introduction of oncological immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs) that transformed the standard of care of several advanced solid malignancies. Using ICIs for advanced gynecological cancers has yielded good results, especially for endometrial cancer. In ovarian or cervical cancer, combining ICIs with other established agents has shown some promise. Concurrently with the clinical development of ICIs, biomarkers that predict responses to such therapy have been discovered and used in clinical trials. The translation of these biomarkers to clinical practice was somewhat hampered by lacking assay standardization and non-comprehensive reporting of biomarker status in trials often performed on a small number of gynecological cancer patients. We can expect increased use of ICIs combined with other agents in gynecological cancer in the near future. This will create a need for reliable response prediction tools, which we believe will be based on biomarker, clinical, and tumor characteristics. In this article, we review the basic biology of ICIs and response prediction biomarkers, as well as the latest clinical trials that focus on subgroup effectiveness based on biomarker status in gynecological cancer patients. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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17 pages, 6665 KiB

Open AccessReview

Estrogens and the Schrödinger’s Cat in the Ovarian Tumor Microenvironment

by Marija Gjorgoska and Tea Lanišnik Rižner

Cancers 2021, 13(19), 5011; https://doi.org/10.3390/cancers13195011 - 6 Oct 2021

Cited by 5 | Viewed by 4703

Abstract

Ovarian cancer is a heterogeneous disease affecting the aging ovary, in concert with a complex network of cells and signals, together representing the ovarian tumor microenvironment. As in the “Schrödinger’s cat” thought experiment, the context-dependent constituents of the—by the time of diagnosis—well-established tumor [...] Read more.

Ovarian cancer is a heterogeneous disease affecting the aging ovary, in concert with a complex network of cells and signals, together representing the ovarian tumor microenvironment. As in the “Schrödinger’s cat” thought experiment, the context-dependent constituents of the—by the time of diagnosis—well-established tumor microenvironment may display a tumor-protective and -destructive role. Systemic and locally synthesized estrogens contribute to the formation of a pro-tumoral microenvironment that enables the sustained tumor growth, invasion and metastasis. Here we focus on the estrogen biosynthetic and metabolic pathways in ovarian cancer and elaborate their actions on phenotypically plastic, estrogen-responsive, aging immune cells of the tumor microenvironment, altogether highlighting the multicomponent-connectedness and complexity of cancer, and contributing to a broader understanding of the ovarian cancer biology. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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