Targeting mesothelin in ovarian cancer.
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ABSTRACT:
SUBMITTER: Ghafoor A
PROVIDER: S-EPMC6281414 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
Publications
Targeting mesothelin in ovarian cancer.
Ghafoor Azam A Thomas Anish A Hassan Raffit R
Oncotarget 20181116 90
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Project description:CAR-macrophage has promising prospect in treating solid tumors, due to its high infiltration into tumors, and its dual roles in phagocytosis and immune modulation. Here we show the clinical results of CAR-macrophage treatment of two ovarian cancer patients. The CAR-macrophages were produced by introducing a mesothelin targeting CAR to patients' primary peripheral blood mononuclear cell-derived macrophages, and the products were infused to patients intravenously. Our data show good safety of the infusion product, and the efficacy can be further improved. Intraperitoneal infusion of CAR-macrophages has proven effective in treating intraperitoneal tumors in a preclinical model, paving the way for demonstrating proof-of-concept clinical efficacy of CAR-macrophages in the treatment of intraperitoneal tumors.
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Project description:Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.
| S-EPMC11244547 | biostudies-literature
Project description:Ovarian cancer is the deadliest gynecological disease among U.S. women. Poor 5-year survival rates (<30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. However, when diagnosed before metastatic propagation the overall 5-year survival rate is >90%. Metastasizing tumor cells grow rapidly and aggressively attach to the mesothelium of all organs within the peritoneal cavity, including the parietal peritoneum and the omentum, producing secondary lesions. In this review, the involvement of mesothelin (MSLN) in the tumor microenvironment is discussed. MSLN, a 40kDa glycoprotein that is overexpressed in many cancers including ovarian and mesotheliomas is suggested to play a role in cell survival, proliferation, tumor progression, and adherence. However, the biological function of MSLN is not fully understood as MSLN knockout mice do not present with an abnormal phenotype. Conversely, MSLN has been shown to bind to the ovarian cancer antigen, CA-125, and thought to play a role in the peritoneal diffusion of ovarian tumor cells. Although the cancer-specific expression of MSLN makes it a potential therapeutic target, more studies are needed to validate the role of MSLN in tumor metastasis.
| S-EPMC6162689 | biostudies-literature
Project description:BackgroundMesothelin is an attractive target for cancer immunotherapy due to its restricted expression in normal tissues and high level expression in several tumor types including ovarian and pancreatic adenocarcinomas. Three mesothelin transcript variants have been reported, but their relative expression in normal tissues and tumors has been poorly characterized. The goal of the present study was to clarify which mesothelin transcript variants are commonly expressed in human tumors.MethodsHuman genomic and EST nucleotide sequences in the public databases were used to evaluate sequences reported for the three mesothelin transcript variants in silico. Subsequently, RNA samples from normal ovary, ovarian and pancreatic carcinoma cell lines, and primary ovarian tumors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing to directly identify expressed transcripts.ResultsIn silico comparisons of genomic DNA sequences with available EST sequences supported expression of mesothelin transcript variants 1 and 3, but there were no sequence matches for transcript variant 2. Newly-derived nucleotide sequences of RT-PCR products from tissues and cell lines corresponded to mesothelin transcript variant 1. Mesothelin transcript variant 2 was not detected. Transcript variant 3 was observed as a small percentage of total mesothelin amplification products from all studied cell lines and tissues. Fractionation of nuclear and cytoplasmic RNA indicated that variant 3 was present primarily in the nuclear fraction. Thus, mesothelin transcript variant 3 may represent incompletely processed hnRNA.ConclusionMesothelin transcript variant 1 represents the predominant mature mRNA species expressed by both normal and tumor cells. This conclusion should be important for future development of cancer immunotherapies, diagnostic tests, and gene microarray studies targeting mesothelin.
| S-EPMC420467 | biostudies-literature
Project description:Study of the hen immune system led to seminal contributions to basic immunological principles. Recent studies of spontaneous ovarian cancer in the laying hen show strikingly similar tumor types and antigen expression compared to human ovarian cancer, suggesting hens would be valuable for studies of tumor immunology and pre-clinical vaccine development. Circulating mesothelin is a relatively specific marker for human ovarian cancer and autoantibodies to mesothelin were reported. We hypothesized that hen tumors express mesothelin and that circulating anti-mesothelin antibodies occur in response to tumors.Mesothelin mRNA expression was analyzed by RT-PCR in hen ovarian tumors and normal ovaries. Mesothelin protein expression was evaluated by immunohistochemistry (IHC) and two-dimensional SDS-PAGE Western blots. Anti-mesothelin antibodies were assessed by immunoassay of sera from hens with normal ovaries and with ovarian tumors.Significant mesothelin mRNA expression was observed in 57% (12/21) of hen ovarian tumors but not in normal ovaries and was found predominantly in serous tumors as in humans. Mesothelin protein was detected in tumors with mesothelin mRNA by IHC and 2D Western blots, but not in normal ovaries or tumors without mesothelin mRNA. Circulating anti-mesothelin antibodies occurred in 44% (n = 4/9) of hens with ovarian tumors which express mesothelin mRNA and were not found in hens with tumors that did not express mesothelin (n = 0/5) or normal ovaries (n = 0/5).The results support the utility of the hen as a novel model for preclinical studies of mesothelin as a biomarker and a target for immunotherapy.
| S-EPMC3163210 | biostudies-literature
Project description:BackgroundHigh-grade serous ovarian cancer (HGSOC) is a highly aggressive malignancy marked by an immunosuppressive tumor microenvironment that hinders effective immune responses. A key feature of this environment is the extensive infiltration of myeloid cells, which contributes to immune evasion. This study explored how mesothelin (MSLN), a tumor-associated antigen, modulates the expression of CD24, an emerging target for immune modulation, and its role in promoting immune evasion in HGSOC. Understanding these underlying mechanisms is crucial for enhancing the efficacy of immune checkpoint blockade (ICB) therapies and improving outcomes in patients with HGSOC.MethodsWe analyzed the expression of MSLN in HGSOC samples and examined its correlation with clinical outcome. In vitro and in vivo models were used to explore how MSLN influences CD24 expression and the polarization of tumor-associated macrophages (TAMs). We also investigated the role of MSLN in the activation of Wnt/β-catenin signaling and its impact on T-cell function and antitumor immunity. The effects of Msln knockdown on CD24 expression and the response to anti-programmed cell death protein-1 (PD-1) therapy were evaluated in syngeneic mouse models.ResultsMSLN expression was found to be significantly elevated in HGSOC, with high MSLN levels correlating with poor prognosis and resistance to ICB. MSLN upregulated CD24 and promoted the protumorigenic polarization of TAMs, contributing to T-cell dysfunction. Mechanistically, MSLN activated Wnt/β-catenin signaling, which in turn enhanced CD24 expression. This activation forms a positive feedback loop that further promotes MSLN transcription. In contrast, Msln knockdown reduced CD24 expression, relieved cytotoxic T-cell suppression, and significantly improved the efficacy of anti-PD-1 therapy in syngeneic models.ConclusionsThis study elucidates the critical role of MSLN in immune evasion in HGSOC and its underlying mechanisms. Targeting MSLN in combination with ICB is a promising strategy to enhance the efficacy of immunotherapy and improve patient outcomes in HGSOC.
| S-EPMC11873354 | biostudies-literature
Project description:BACKGROUND: Although dendritic cell (DC) vaccines are considered to be promising treatments for advanced cancer, their production and administration is costly and labor-intensive. We developed a novel immunotherapeutic agent that links a single-chain antibody variable fragment (scFv) targeting mesothelin (MSLN), which is overexpressed on ovarian cancer and mesothelioma cells, to Mycobacterium tuberculosis (MTB) heat shock protein 70 (Hsp70), which is a potent immune activator that stimulates monocytes and DCs, enhances DC aggregation and maturation and improves cross-priming of T cells mediated by DCs. METHODS: Binding of this fusion protein with MSLN on the surface of tumor cells was measured by flow cytometry and fluorescence microscopy. The therapeutic efficacy of this fusion protein was evaluated in syngeneic and orthotopic mouse models of papillary ovarian cancer and malignant mesothelioma. Mice received 4 intraperitoneal (i.p.) treatments with experimental or control proteins post i.p. injection of tumor cells. Ascites-free and overall survival time was measured. For the investigation of anti-tumor T-cell responses, a time-matched study was performed. Splenocytes were stimulated with peptides, and IFN?- or Granzyme B- generating CD3+CD8+ T cells were detected by flow cytometry. To examine the role of CD8+ T cells in the antitumor effect, we performed in vivo CD8+ cell depletion. We further determined if the fusion protein increases DC maturation and improves antigen presentation as well as cross-presentation by DCs. RESULTS: We demonstrated in vitro that the scFvMTBHsp70 fusion protein bound to the tumor cells used in this study through the interaction of scFv with MSLN on the surface of these cells, and induced maturation of bone marrow-derived DCs. Use of this bifunctional fusion protein in both mouse models significantly enhanced survival and slowed tumor growth while augmenting tumor-specific CD8+ T-cell dependent immune responses. We also demonstrated in vitro and in vivo that the fusion protein enhanced antigen presentation and cross-presentation by targeting tumor antigens towards DCs. CONCLUSIONS: This new cancer immunotherapy has the potential to be cost-effective and broadly applicable to tumors that overexpress mesothelin.
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Project description:Peritoneal dissemination is a particular form of metastasis typically observed in ovarian cancer and the major cause for poor patient's outcome. Identification of the molecular players involved in ovarian cancer dissemination can offer an approach to develop treatment strategies to improve clinical prognosis. Here, we identified mesothelin (MSLN) as a crucial protein in the multistep process of peritoneal dissemination of ovarian cancer. We demonstrated that MSLN is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas (HGSC). Using several genetically engineered ovarian cancer cell lines, resulting in loss or gain of function, we found that MSLN increased cell survival in suspension and invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLNhigh ovarian cancer cell lines showed enhanced tumor burden and spread within the peritoneal cavity. These findings provide strong evidences that MSLN is a key player in ovarian cancer progression by triggering peritoneal dissemination and provide support for further clinical investigation of MSLN as a therapeutic target in HGSC.
| S-EPMC7329842 | biostudies-literature
Project description:Mesothelin (MSLN) is a differentiation antigen that is highly expressed in many epithelial cancers. MSLN is an important therapeutic target due to its high expression in cancers and limited expression in normal human tissues. Although it has been assumed that shed antigen is a barrier to immunotoxin action, a modeling study predicted that shed MSLN may enhance the action of MSLN-targeting recombinant immunotoxins such as SS1P and similar therapeutics by facilitating their redistribution within tumors. We aimed to determine whether shed MSLN enhances or reduces the antitumor effect of MSLN-targeting immunotoxins SS1P and RG7787. We engineered a cell line, A431/G9 (TACE mutant) that expresses a mutant form of MSLN in which the TNF-converting enzyme protease site is replaced with GGGS. We compared the response of the TACE-mutant cells with immunotoxins SS1P and RG7787 with that of the parental A431/H9 cell line. We show that TACE-mutant cells shed 80% less MSLN than A431/H9 cells, that TACE-mutant cells show a 2- to 3-fold increase in MSLN-targeted immunotoxin uptake, and that they are about 5-fold more sensitive to SS1P killing in cell culture. Tumors with reduced shedding respond significantly better to treatment with SS1P and RG7787. Our data show that MSLN shedding is an impediment to the antitumor activity of SS1P and RG7787. Approaches that decrease MSLN shedding could enhance the efficacy of immunotoxins and immunoconjugates targeting MSLN-expressing tumors. Mol Cancer Ther; 15(7); 1648-55. ©2016 AACR.
| S-EPMC4936933 | biostudies-literature
Project description:Intraperitoneal cellular immunotherapy with CAR-redirected lymphocytes is an intriguing approach to target peritoneal carcinomatosis (PC) from ovarian cancer (OC), which is currently evaluated in clinical trials. PC displays a composite structure with floating tumor cells within ascites and solid-like masses invading the peritoneum. Therefore, a comprehensive experimental model is crucial to optimize CAR-cell therapies in such a peculiar environment. Here, we explored the activity of cytokine-induced killer lymphocytes (CIK), redirected by CAR against mesothelin (MSLN-CAR.CIK), within reductionistic 3D models resembling the structural complexity of both liquid and solid components of PC. MSLN-CAR.CIK effectively killed and were functionally efficient against OC targets. In a "floating-like" 3D context with floating OC spheroids, both tumor localization and killing by MSLN-CAR.CIK were significantly boosted by fluid flow. In a "solid-like" context, MSLN-CAR.CIK were recruited through the extracellular matrix on embedded tumor aggregates, with variable kinetics depending on the effector-target distance. Furthermore, MSLN-CAR.CIK penetrated the inner levels of OC spheroids exerting effective tumor killing. Our findings provide currently unknown therapeutically relevant information on intraperitoneal approaches with CAR.CIK, supporting further developments and improvements for clinical studies in the context of locoregional cell therapy approaches for patients with PC from OC.
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