Ovarian malignant ascites-derived lymphocytes stimulated with prothymosin α or its immunoactive decapeptide lyse autologous tumour cells in vitro and retard tumour growth in SCID mice

Voutsas, Ioannis F.; Pistamaltzian, Nikolaos; Tsiatas, Marinos; Skopeliti, Margarita; Κάτσιλα, Θεοδώρα; Mavrothalassiti, Ilektra; Spyrou, Spyros I.; Dimopoulos, Meletios Α.; Tsitsilonis, Ourania E.; Bamias, Aristotelis

doi:10.1016/j.ejca.2012.11.037

Cited by 12 publications

(6 citation statements)

References 33 publications

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“…Ascites-associated T cells in human and mouse OC have been shown to include tumor-reactive T cells. 23 To test whether ex vivo activated ascites monocytes could efficiently cross-present autologous tumor antigen previously acquired in vivo, TLR-activated ascites monocytes were cocultured with autologous TALs isolated from the same ascites samples. T cell activation was assessed through IFN-γ secretion.…”

Section: Resultsmentioning

confidence: 99%

Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes

Adams

Grimm

Chiang

et al. 2020

J Immunother Cancer

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BackgroundNovel therapeutic strategies in ovarian cancer (OC) are needed as the survival rate remains dismally low. Although dendritic cell-based cancer vaccines are effective in eliciting therapeutic responses, their complex and costly manufacturing process hampers their full clinical utility outside specialized clinics. Here, we describe a novel approach of generating a rapid and effective cancer vaccine using ascites-derived monocytes for treating OC.MethodsUsing the ID8 mouse ovarian tumor model and OC patient samples, we isolated ascites monocytes and evaluated them with flow cytometry, Luminex cytokine and chemokine array analysis, ex vivo cocultures with T cells, in vivo tumor challenge and T cell transfer experiments, RNA-sequencing and mass spectrometry.ResultsWe demonstrated the feasibility of isolating ascites monocytes and restoring their ability to function as bona fide antigen-presenting cells (APCs) with Toll-like receptor (TLR) 4 lipopolysaccharide and TLR9 CpG-oligonucleotides, and a blocking antibody to interleukin-10 receptor (IL-10R Ab) in the ID8 model. The ascites monocytes were laden with tumor antigens at a steady state in vivo. After a short 48 hours activation, they upregulated maturation markers (CD80, CD86 and MHC class I) and demonstrated strong ex vivo T cell stimulatory potential and effectively suppressed tumor and malignant ascites in vivo. They also induced protective long-term T cell memory responses. To evaluate the translational potential of this approach, we isolated ascites monocytes from stage III/IV chemotherapy-naïve OC patients. Similarly, the human ascites monocytes presented tumor-associated antigens (TAAs), including MUC1, ERBB2, mesothelin, MAGE, PRAME, GPC3, PMEL and TP53 at a steady state. After a 48-hour treatment with TLR4 and IL-10R Ab, they efficiently stimulated oligoclonal tumor-associated lymphocytes (TALs) with strong reactivity against TAAs. Importantly, the activated ascites monocytes retained their ability to activate TALs in the presence of ascitic fluid.ConclusionsAscites monocytes are naturally loaded with tumor antigen and can perform as potent APCs following short ex vivo activation. This novel ascites APC vaccine can be rapidly prepared in 48 hours with a straightforward and affordable manufacturing process, and would be an attractive therapeutic vaccine for OC.

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Section: Resultsmentioning

confidence: 99%

Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes

Adams

Grimm

Chiang

et al. 2020

J Immunother Cancer

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“…Prothymosin alpha (PTMA) is a nuclear oncoprotein commonly used as a prognostic marker in many tumor types . In ovarian cancers, PTMA increases the CD8+ T‐cell–mediated lysis of tumor cells, and inhibits tumor growth of orthotopic tumors in SCID mice …”

Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Novel Protein Biomarkers in Ovarian Cancer Patient Urine

Sandow

Rainczuk

Infusini

et al. 2018

Proteomics Clinical Apps

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“…Besides DCs, proTα could also activate other immune cell types expressing TLR4, eg, neutrophils to secrete Á O 2 À and kill tumor cells in vitro , and macrophages (Mosoian et al, 2010). Ex vivo experiments showed that proTα significantly restored the reduced cytotoxicity of immunosuppressed ascites-derived tumorassociated lymphocytes against ovarian tumor cells and inhibited ovarian tumor growth in SCID mice inoculated with human tumors (Voutsas et al, 2013).…”

Section: The Thoroughly Studied Anticancer Activity Of Protαmentioning

confidence: 99%

“…The C-terminal decapeptide proTα(100-109) (TKKQKTDEDD) was identified by our research team as the immunoactive area of the polypeptide and a potent lymphocyte stimulator (Skopeliti et al, 2006). ProTα (100-109) has been shown to stimulate PBMC proliferation and cytotoxicity and to promote the phenotypic maturation of DCs (Skopeliti et al, 2009), and, consequently, it improved the functionality of immunogenic peptide-pulsed DCs, induced T H 1-type immune response polarization , augmented basic properties of human neutrophils , enhanced the depressed cytotoxicity of tumor-associated lymphocytes against autologous tumor cells in vitro, and retarded tumor growth in vivo (Voutsas et al, 2013). Using as control a scrambled decapeptide with the same amino acid composition but a different primary structure, the immunoenhancing activity of proTα(100-109) was shown to be sequence-specific and comparable to that of intact proTα.…”

Section: The Carboxy-terminal Protα Peptides Exhibit Improved Immune mentioning

confidence: 99%

Prothymosin Alpha and Immune Responses

Samara

Ioannou

Tsitsilonis

2016

Vitamins and Hormones

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The thymus gland produces soluble molecules, which mediate significant immune functions. The first biologically active thymic extract was thymosin fraction V, the fractionation of which led to the isolation of a series of immunoactive polypeptides, including prothymosin alpha (proTα). ProTα displays a dual role, intracellularly as a survival and proliferation mediator and extracellularly as a biological response modifier. Accordingly, inside the cell, proTα is implicated in crucial intracellular circuits and may serve as a surrogate tumor biomarker, but when found outside the cell, it could be used as a therapeutic agent for treating immune system deficiencies. In fact, proTα possesses pleiotropic adjuvant activity and a series of immunomodulatory effects (eg, anticancer, antiviral, neuroprotective, cardioprotective). Moreover, several reports suggest that the variable activity of proTα might be exerted through different parts of the molecule. We first reported that the main immunoactive region of proTα is the carboxy-terminal decapeptide proTα(100-109). In conjunction with data from others, we also revealed that proTα and proTα(100-109) signal through Toll-like receptor 4. Although their precise molecular mechanism of action is yet not fully elucidated, proTα and proTα(100-109) are viewed as candidate adjuvants for cancer immunotherapy. Here, we present a historical overview on the discovery and isolation of thymosins with emphasis on proTα and data on some immune-related new activities of the polypeptide and smaller immunostimulatory peptides thereof. Finally, we propose a compiled scenario on proTα's mode of action, which could eventually contribute to its clinical application.

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Ovarian malignant ascites-derived lymphocytes stimulated with prothymosin α or its immunoactive decapeptide lyse autologous tumour cells in vitro and retard tumour growth in SCID mice

Cited by 12 publications

References 33 publications

Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes

Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes

Discovery and Validation of Novel Protein Biomarkers in Ovarian Cancer Patient Urine

Prothymosin Alpha and Immune Responses

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