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      Endometrial Stromal Sarcomas: A Revision of Their Potential as Targets for Immunotherapy

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          Abstract

          Endometrial stromal sarcomas are a subtype of uterine sarcomas that are characterized by recurrent chromosomal translocations, resulting in the expression of tumor-specific fusion proteins that contribute to their tumorigenicity. These characteristics make the translocation breakpoints promising targets for immunotherapeutic approaches. In this review, we first describe the current knowledge about the classification of endometrial stromal sarcomas, and their molecular and genetic characteristics. Next, we summarize the available data on the use of translocation breakpoints as immunotherapeutic targets. Finally, we propose a roadmap to evaluate the feasibility of immunologic targeting of the endometrial stromal sarcoma-specific translocations in patients with recurrent disease.

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          Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice.

          Pawel Muranski, Nicholas Restifo, C. Palmer … (2011)
          Adoptive cell transfer (ACT) of tumor infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen restimulation, and common gamma-chain (γ(c)) cytokine support. However, the relative contributions of each these individual components to the magnitude of the antitumor response have yet to be quantified. To systematically and quantitatively appraise each of these variables, we employed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen restimulation, we also evaluated the relative efficacy of central memory (T(CM)), effector memory (T(EM)), and stem cell memory (T(SCM)) subsets on the strength of tumor regression as well as the dose and type of clinically available γ(c) cytokines, including IL-2, IL-7, IL-15, and IL-21. We found that cell dose, T-cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (≥6 doses) administration was observed. Moreover, the specific type and dose of γ(c) cytokine only moderately correlated with response. Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further show that γ(c) cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo. ©2011 AACR.
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            14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma.

            Frédéric Amant, M Nucci, Sohrab Shah … (2012)
            14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE-FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE-FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE-FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE-FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE-FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions.
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              Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors.

              A Soreng, Chia-Chun Kuo, Colton J. Koontz … (2001)
              Endometrial stromal tumors are divided into three types: benign stromal nodules, endometrial stromal sarcomas, and undifferentiated endometrial sarcomas. A variety of cytogenetic abnormalities involving chromosome 7 have been reported in endometrial stromal sarcomas, including a recurrent t(7;17)(p15;q21). We have identified two zinc finger genes, which we have termed JAZF1 and JJAZ1, at the sites of the 7p15 and 17q21 breakpoints. Analyses of tumor RNA indicate that a JAZF1/JJAZ1 fusion is present in all types of endometrial stromal tumors; however, the fusion appears to be rarer among endometrial stromal sarcomas that would be considered high-grade according to certain classification schemes. These findings suggest that the less malignant endometrial stromal tumors may evolve toward more malignant types, but that some endometrial stromal sarcomas with relatively abundant mitotic activity may compose a biologically distinct group.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Vaccines (Basel)
                Journal ID (iso-abbrev): Vaccines (Basel)
                Journal ID (publisher-id): vaccines
                Title: Vaccines
                Publisher: MDPI
                ISSN (Electronic): 2076-393X
                Publication date (Electronic): 25 August 2018
                Publication date Collection: September 2018
                Volume: 6
                Issue: 3
                Electronic Location Identifier: 56
                Affiliations
                [1 ]Division of Gynecologic Oncology, Department of Oncology, KU Leuven, 3000 Leuven, Belgium; frederic.amant@ 123456uzleuven.be
                [2 ]Leuven Cancer Institute (LKI), 3000 Leuven, Belgium
                [3 ]Division of Gynecology & Obstetrics, UZ Leuven, 3000 Leuven, Belgium
                [4 ]Center for Gynecologic Oncology Amsterdam (CGOA), Antoni Van Leeuwenhoek-Netherlands Cancer Institute (Avl-NKI) and University Medical Centra (UMC), 1066 CX Amsterdam, The Netherlands
                Author notes
                [* ]Correspondence: sandra.tuyaerts@ 123456kuleuven.be ; Tel.: +32-16-342905
                Author information
                https://orcid.org/0000-0003-1255-8071
                Article
                Publisher ID: vaccines-06-00056
                DOI: 10.3390/vaccines6030056
                PMC ID: 6161160
                PubMed ID: 30149610
                SO-VID: 24df4221-ca22-44f0-8248-28c13442a152
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 13 July 2018
                Date accepted : 22 August 2018
                Categories
                Subject: Review

                Keywords: endometrial stromal sarcoma,recurrent chromosomal translocations,neoantigen,immunotherapy
                Data availability:
                Keywords: endometrial stromal sarcoma, recurrent chromosomal translocations, neoantigen, immunotherapy

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