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Combined chemotherapy and allogeneic human V?9V?2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo.

ABSTRACT: Epithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate <35%). Diagnosis of EOC is frequently made at advanced stages and, despite aggressive treatments combining surgery and chemotherapy, fatal relapse rapidly occurs and is accompanied by a peritoneal carcinosis. In this context, novel therapeutical advances are urgently required. Adoptive transfer(s) of immune effector cells, including allogeneic human V?9V?2 T lymphocytes, represent attractive targets for efficiently and safely tracking tissue-invading tumor cells and controlling tumor dissemination in the organism. Our study describes the establishment of robust and physiological orthotopic model of human EOC in mouse, that includes surgical resection (ovariectomy) and chemotherapy, which are ineluctably accompanied by a fatal peritoneal carcinosis recurrence. Through a complementary set of in vitro and in vivo experiments, we provide here a preclinical proof of interest of the antitumor efficiency of adoptive transfers of allogeneic human V?9V?2 T lymphocytes against EOC, in association with surgical debulking and standard chemotherapies (i.e., taxanes and platinum salts). Moreover, our results indicate that chemo- and immunotherapies can be combined to improve the antitumor efficiency of immunotherapeutic lines. Altogether, these results further pave the way for next-generation antitumor immunotherapies, based on local administrations of human allogeneic human V?9V?2 T lymphocytes, in association with standard treatments.

SUBMITTER: Joalland N

PROVIDER: S-EPMC6791416 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells <i>in vivo</i>.

Joalland Noémie N Lafrance Laura L Oullier Thibauld T Marionneau-Lambot Séverine S Loussouarn Delphine D Jarry Ulrich U Scotet Emmanuel E

Oncoimmunology 20190828 11

Epithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate <35%). Diagnosis of EOC is frequently made at advanced stages and, despite aggressive treatments combining surgery and chemotherapy, fatal relapse rapidly occurs and is accompanied by a peritoneal carcinosis. In this context, novel therapeutical advances are urgently required. Adoptive transfer(s) of immune effector cells, inc ...[more]

PMID: 31646097

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Project description:BackgroundThe mortality rate of ovarian cancer ranks first among three common gynecological malignant tumors due to insidious onset and lack of effective early diagnosis methods. Borderline epithelial ovarian tumor (BEOT) is a type of low malignant potential tumor that is typically associated with better outcomes than ovarian cancer. However, BEOTs are easily confused with benign and malignant epithelial ovarian tumors (EOTs) due to similar clinical symptoms and lack of specific tumor biomarkers and imaging examinations. Notably, a small subset of BEOTs will transform into low-grade serous ovarian carcinoma with a poor prognosis. Therefore, searching for potential biomarkers that can be easily obtained and accurately identify malignant epithelial ovarian tumors (MEOTs) as well as BEOTs is essential for the clinician. Cancer antigen 125 (CA125) is a commonly used biomarker for the diagnosis of EOTs in the preoperative scenario but has low sensitivity and specificity. Nowadays, inflammatory biomarkers including inflammatory cell counts and derived ratios such as neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been proved to be associated with tumor progression and poor prognosis, and were considered to be the most economically potential surrogate biomarkers for various malignancies. The purpose of this study was to find appropriate combinations of inflammatory and tumor biomarkers to improve the diagnostic efficiency of EOTs, especially the BEOTs.ResultsCA125, NLR and PLR increased steadily among benign, borderline and malignant EOTs and tended to be higher in advanced (stage III-IV) and lymph node metastasis MEOT groups than in early stage (stage I-II) and non-lymph node metastasis MEOT groups. CA125, NLR and PLR could be used separately in the differentiation of EOTs but could not take into account both sensitivity and specificity. The combined use of CA125, NLR and PLR was evaluated to be more efficient, especially in the identification of BEOTs, with both high sensitivity and high specificity.ConclusionsThe levels of CA125, NLR and PLR were closely related to the nature of EOTs and malignant progression of MEOTs. The combination of CA125, NLR and PLR was more accurate in identifying the nature of EOTs than either alone or double combination, especially for BEOTs.

Project description:BackgroundHuman amniotic epithelial cells (hAECs) are attractive candidates for regenerative medical therapy, with the potential to replace deficient cells and improve functional recovery after injury. Previous studies have demonstrated that transplantation of hAECs effectively alleviate chemotherapy-induced ovarian damage via inhibiting granulose cells apoptosis in animal models of premature ovarian failure/insufficiency (POF/POI). However, the underlying molecular mechanism accounting for hAECs-mediated ovarian function recovery is not fully understood.MethodsTo investigate whether hAECs-secreting cytokines act as molecular basis to attenuate chemotherapy-induced ovarian injury, hAECs or hAEC-conditioned medium (hAEC-CM) was injected into the unilateral ovary of POF/POI mouse. Follicle development was evaluated by H&E staining at 1, 2 months after hAECs or hAEC-CM treatment. In addition, we performed a cytokine array containing 507 human cytokines on hAECs-derived serum-free conditioned medium. Finally, we further investigated whether hAECs could affect chemotherapy-induced apoptosis in primary human granulosa-lutein (hGL) cells and the tube formation of human umbilical vein endothelial cells (hUVECs) via a co-culture system in vitro.ResultsWe observed the existence of healthy and mature follicles in ovaries treated with hAECs or hAEC-CM, whereas seriously fibrosis and many atretic follicles were found in the contralateral untreated ovaries of the same mouse. To distinguish cytokines involved in the process of hAECs-restored ovarian function, hAEC-CM was analyzed with a human cytokines array. Results revealed that 109 cytokines in hAEC-CM might participate in a variety of biological processes including apoptosis, angiogenesis, cell cycle and immune response. In vitro experiments, hAECs significantly inhibited chemotherapy-induced apoptosis and activated TGF-β/Smad signaling pathway within primary granulosa-lutein cells in paracrine manner. Furthermore, hAEC-CM was shown to promote angiogenesis in the injured ovaries and enhance the tube formation of human umbilical vein endothelial cells (hUVECs) in co-culture system.ConclusionsThese findings demonstrated that paracrine might be a key pathway in the process of hAECs-mediating ovarian function recovery in animal models of premature ovarian failure/insufficiency (POF/POI).

Dataset Information

Combined chemotherapy and allogeneic human V?9V?2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo.

Publications

Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells <i>in vivo</i>.

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