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Immune modulation in serous epithelial ovarian cancer: focus on the role of tumor-derived exosomes
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Serous epithelial ovarian cancer (EOC) is a potent suppressor of the immune defense. Here, we studied interactions between EOC and the immune system that lead to escape from tumor immune surveillance. We explored: 1) tumor escape from cytotoxicity by exosome-mediated modulation of the NK-cell receptors NKG2D and DNAM-1; 2) cytokine mRNA profiles in the EOC microenvironment and peripheral blood and their role in the suppression of the anti-tumor immune responses; 3) expression of long non-coding (lnc) RNAs in EOC tumors and exosomes.

We found that EOC-secreted exosomes carried MICA/B and ULBP1-3, ligands of NKG2D, and could downregulate the NKG2D receptor and impair NKG2D-mediated cytotoxicity. In contrast, the DNAM-1 receptor ligands PVR and nectin-2 were seldom found in exosomes and were not associated with the exosomal membrane leaving the DNAM-1 receptor-mediated cytotoxicity intact. We compared cytokine mRNA expression in the tumor microenvironment and in immune cells of peripheral blood in EOC patients and patients with benign ovarian conditions. EOC patients were unable to mount an IFN-gamma mRNA response needed for tumor cell elimination. Instead, there was a significant up-regulation of inflammation and immune suppression i.e. responses promoting tumorigenesis and T-regulatory cell priming that suppress anti-tumor immunity. In addition, we studied lncRNAs in tissues and sera exosomes from EOC and benign ovarian conditions aiming to assess the lncRNA(s) expression profile and look for lncRNA(s) as possible marker(s) for early diagnosis. We found a deregulated lncRNAs expression in EOC tissues that correlated well with the lncRNAs expression in exosomes. Candidate lncRNAs with the highest expression and abundance were suggested for evaluation as EOC diagnostic markers in a future large cohort study.

Our studies of EOC tissue and EOC exosomes highlight the immunosuppressive tumor microenvironment and the complex tumor exosome-mediated network of immunosuppressive mechanisms, and provide a mechanistic explanation of the observation that NKG2D-mediated cytotoxicity does not function in EOC patients and is partially replaced by the accessory DNAM-1 dependent cytotoxic pathway. The deregulated lncRNAs expression in EOC tissues and exosomes might serve for diagnostic purposes but could also be a potential risk of spreading tumor-derived lncRNAs in EOC exosomes to recipient cells throughout the body.

Ort, förlag, år, upplaga, sidor
Umeå: Umea University , 2017. , s. 68
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1901
Nyckelord [en]
ovarian cancer, EOC, HGSC, exosomes, NKG2D, MICA/B, ULBP, DNAM-1, PVR, nectin-2, lncRNAs, immune suppression, anti-tumor immunity, NK-cell cytotoxicity, cytokines, Th1, Th2, T regulatory response, inflammation, tumor microenvironment
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-138264ISBN: 978-91-7601-731-9 (tryckt)OAI: oai:DiVA.org:umu-138264DiVA, id: diva2:1133506
Disputation
2017-09-15, Horsal D, Unod T9, Norrland's Universitetssjukhus, Umea, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-08-25 Skapad: 2017-08-16 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Delarbeten
1. Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity
Öppna denna publikation i ny flik eller fönster >>Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity
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2016 (Engelska)Ingår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, nr 4, s. 5455-5466Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cancers constitutively produce and secrete into the blood and other biofluids 30-150 nm-sized endosomal vehicles called exosomes. Cancer-derived exosomes exhibit powerful influence on a variety of biological mechanisms to the benefit of the tumors that produce them. We studied the immunosuppressive ability of epithelial ovarian cancer (EOC) exosomes on two cytotoxic pathways of importance for anticancer immunity-the NKG2D receptor-ligand pathway and the DNAM-1-PVR/nectin-2 pathway. Using exosomes, isolated from EOC tumor explant and EOC cell-line culture supernatants, and ascitic fluid from EOC patients, we studied the expression of NKG2D and DNAM-1 ligands on EOC exosomes and their ability to downregulate the cognate receptors. Our results show that EOC exosomes differentially and constitutively express NKG2D ligands from both MICA/B and ULBP families on their surface, while DNAM-1 ligands are more seldom expressed and not associated with the exosomal membrane surface. Consequently, the NKG2D ligand-bearing EOC exosomes significantly downregulated the NKG2D receptor expression on peripheral blood mononuclear cells (PBMC) while the DNAM-1 receptor was unaffected. The downregulation of NKG2D receptor expression was coupled to inhibition of NKG2D receptor-ligand-mediated degranulation and cytotoxicity measured in vitro with OVCAR-3 and K562 cells as targets. The EOC exosomes acted as a decoy impairing the NKG2D mediated cytotoxicity while the DNAM-1 receptor-ligand system remained unchanged. Taken together, our results support and explain the mechanism behind the recently reported finding that in EOC, NK-cell recognition and killing of tumor cells was mainly dependent on DNAM-1 signaling while the contribution of the NKG2D receptor-ligand pathway was complementary and uncertain.

Nyckelord
Epithelial ovarian cancer/EOC, Tumor, Exosomes, NKG2D, DNAM-1/CD266, Cytotoxicity, MICA/B, ULBP, PVR, Nectin-2
Nationell ämneskategori
Cancer och onkologi Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-118529 (URN)10.1007/s13277-015-4313-2 (DOI)000374904500128 ()26563374 (PubMedID)2-s2.0-84946924480 (Scopus ID)
Tillgänglig från: 2016-03-22 Skapad: 2016-03-22 Senast uppdaterad: 2023-03-23Bibliografiskt granskad
2. Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary
Öppna denna publikation i ny flik eller fönster >>Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary
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2017 (Engelska)Ingår i: Journal of Cancer Science & Therapy, ISSN 1948-5956, Vol. 9, nr 5, s. 422-429Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objective: Tumor establishment, metastatic spreading and poor survival in ovarian cancer is strongly associated with progressive derangement of the patient’s immune system. Accumulating evidence suggests that immune impairment is influenced by the production and presence of cytokines in the tumor microenvironment. Methods: Cytokine mRNA profiles in tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed in patients with high grade serous carcinoma (HGSC) of the ovary and compared it to patients with benign ovarian conditions and controls with normal ovaries. Cytokine assessment was done by real-time quantitative RT-PCR and specific primers and probes for 12 cytokines-IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, TNF-β/LTA, TGF-β1, and GM-CSF chosen to distinguish between cytotoxic Th1, humoral Th2, regulatory Th3/Tr1 and inflammatory responses. Results: The cytokine mRNA response in the HGSC patients was significantly up regulated compared to patients with benign ovarian conditions and normal ovary controls confirming the immunogenicity of HGSC and implying immune recognition and reaction locally in the tumor microenvironment and systemically in the peripheral blood.There was an up-regulation of inflammatory and inhibitory cytokine mRNA promoting tumor progression, T-regulatory cell priming and T-regulatory cell-mediated immune suppression. In contrast, there was an inability to mount the crucially important IFN gamma response needed for upregulation of the cytotoxic anti-tumor response in the local microenvironment. In addition, systemic IL-4- mediated Th2 response prevailed in the peripheral blood deviating the systemic defense towards humoral immunity. Conclusions: Taken together, these results suggest local and systemic cytokine cooperation promoting tumor survival, progression and immune escape. Our study confirms and extends previous investigations and contributes to the evaluation of potential cytokine candidates for diagnostic cytokine mRNA profiles and for future therapeutic interventions based on cytokine inhibition.

Nyckelord
Cytokines, High-grade serous ovarian carcinoma (HGSC), EOC, Tumor microenvironment, Tumor inflammation, Immune suppression
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-138256 (URN)10.4172/1948-5956.1000453 (DOI)
Tillgänglig från: 2017-08-15 Skapad: 2017-08-15 Senast uppdaterad: 2021-03-02Bibliografiskt granskad
3. Deregulated expression of lncRNAs in epithelial ovarian cancer tissue can be revealed by probing circulating exosomes: A possible novel approach to cancer diagnosis
Öppna denna publikation i ny flik eller fönster >>Deregulated expression of lncRNAs in epithelial ovarian cancer tissue can be revealed by probing circulating exosomes: A possible novel approach to cancer diagnosis
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-138263 (URN)
Tillgänglig från: 2017-08-16 Skapad: 2017-08-16 Senast uppdaterad: 2017-08-16

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Labani Motlagh, Alireza

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