Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Israelsson, Pernilla
Publications (10 of 10) Show all publications
Gideonsson, I., Israelsson, P., Strandberg, S. & Ottander, U. (2023). Long-term follow-up of tamoxifen treatment and the use of imaging in psammocarcinoma: a case report, review of the literature and discussion of diagnostic and therapeutic challenges. Current Oncology, 30(12), 10260-10271
Open this publication in new window or tab >>Long-term follow-up of tamoxifen treatment and the use of imaging in psammocarcinoma: a case report, review of the literature and discussion of diagnostic and therapeutic challenges
2023 (English)In: Current Oncology, ISSN 1198-0052, E-ISSN 1718-7729, Vol. 30, no 12, p. 10260-10271Article in journal (Refereed) Published
Abstract [en]

Psammocarcinoma (PsC) represents a rare form of low-grade serous tumor of the ovary or peritoneum. Although ovarian cancer generally has a poor prognosis in its late stages, PsC seems to have a more indolent course. We present a patient with a history of unspecific abdominal pain for more than a year, with sudden acute onset of severe inguinal pain. On admission to the hospital, a computed tomography (CT) revealed a pelvic mass of suspected ovarian origin. Radical surgery was attempted but not achieved due to widespread tumor growth. Histopathological evaluation revealed estrogen receptor-positive stage III PsC. Tamoxifen treatment was thus initiated, still maintaining stable disease 10 years later. The patient has undergone extensive radiological work-up, including CT, chest X-ray, 18F-fluoro-deoxy-glucose positron emission tomography (PET)/CT, 99mTc- hydroxymethylene diphosphonate (HDP) bone scintigraphy, 18F-fluoro-thymidine (FLT) PET/CT, Tc-99m depreotide scintigraphy and magnetic resonance imaging. In conclusion, we demonstrate that PsC has characteristic radiological features and different imaging modalities can be suitable in different clinical situations. In contrast to most other ovarian cancers, PsC does not always warrant adjuvant chemotherapy, even in advanced stages. This emphasizes the need for a deeper knowledge of the biological behavior of this rare tumor, to select the optimal treatment strategy.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
case report, CT, FDG PET, imaging, MRI, ovarian cancer, psammocarcinoma, psammoma bodies, serous carcinoma, tamoxifen
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-219099 (URN)10.3390/curroncol30120747 (DOI)38132381 (PubMedID)2-s2.0-85180702524 (Scopus ID)
Funder
Umeå University
Available from: 2024-01-10 Created: 2024-01-10 Last updated: 2024-01-10Bibliographically approved
Israelsson, P., Björk, E., Nagaev, I., Nagaeva, O., Lundin, E., Mincheva-Nilsson, L. & Ottander, U. (2023). NKG2D-mediated cytotoxicity improves after primary surgery for high-grade serous ovarian cancer. American Journal of Reproductive Immunology, 89(1), Article ID e13647.
Open this publication in new window or tab >>NKG2D-mediated cytotoxicity improves after primary surgery for high-grade serous ovarian cancer
Show others...
2023 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 89, no 1, article id e13647Article in journal (Refereed) Published
Abstract [en]

Problem: Tumors compromise the patients’ immune system to promote their own survival. We have previously reported that HGSC exosomes play a central role, downregulating NKG2D cytotoxicity. Primary surgery's effect on tumor exosomes and NKG2D cytotoxicity in HGSC patients has not been studied before. The overall objective of this study was to explore the effect of surgery on the exosome-induced impairment of NKG2D cytotoxicity in HGSC.

Method of study: Paired pre- and post-operative blood samples were subjected to cell and exosome analyses regarding the NKG2D receptor and ligands, and NKG2D-mediated cytotoxicity. Lymphocytes were phenotyped by immunoflow cytometry. Exosomes, isolated by ultracentrifugation, and characterized by nanoparticle tracking analysis, transmission and immune electron microscopy and western blot were used in functional cytotoxic experiments. HGSC explant culture-derived exosomes, previously studied by us, were used for comparison.

Results: HGSC exosomes from patients’ sera downregulated NKG2D-mediated cytotoxicity in NK cells of healthy donors. In a subgroup of subjects, NKG2D expression on CTLs and NK cells was upregulated after surgery, correlating to a decrease in the concentration of exosomes in postoperative sera. An overall significantly improved NKG2D-mediated cytotoxic response of the HGSC patients’ own NK cells in postoperative compared to preoperative samples was noted.

Conclusions: Surgical removal of the primary tumor has a beneficial effect, relieving the exosome-mediated suppression of NKG2D cytotoxicity in HGSC patients, thus boostering their ability to combat cancer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
cytotoxicity, EOC/HGSC, epithelial ovarian cancer, exosomes, immune suppression, NKG2D, NKG2D ligands, surgery
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-201334 (URN)10.1111/aji.13647 (DOI)000888859600001 ()36335434 (PubMedID)2-s2.0-85142285991 (Scopus ID)
Funder
Swedish Research Council, 18-20–345240311Swedish Cancer Society, CAN 2018/350; no. 18 07 17
Available from: 2022-12-15 Created: 2022-12-15 Last updated: 2022-12-30Bibliographically approved
Green, C., Mettävainio, M. I., Kjellman, C., Ramqvist, T., Dalianis, T., Israelsson, P. & Lindquist, D. (2022). Combined treatment with radiotherapy, chemotherapy and avelumab results in regression of metastatic Merkel cell carcinoma and improvement of associated Lambert‑Eaton myasthenic syndrome: a case report. Oncology Letters, 24(5), Article ID 393.
Open this publication in new window or tab >>Combined treatment with radiotherapy, chemotherapy and avelumab results in regression of metastatic Merkel cell carcinoma and improvement of associated Lambert‑Eaton myasthenic syndrome: a case report
Show others...
2022 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 24, no 5, article id 393Article in journal (Refereed) Published
Abstract [en]

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy arising from mecha‑ noreceptors in the basal epidermis. Due to a pronounced risk of spread and a high propensity for recurrence after treatment, immediate treatment is of utmost importance. Lambert‑Eaton myasthenic syndrome (LEMS) is a paraneoplastic phenom‑ enon affecting the muscles with autoimmune pathophysiology, and >50% of known cases are associated with an underlying malignancy. In the present report, the case of a 67‑year‑old man presenting with progressive proximal muscle weakness, auto‑ nomic dysfunction and involuntary weight loss is described. Symptoms and detection of voltage‑gated calcium channel antibodies were consistent with LEMS. Distant metastases were found in the inguinal and iliac lymph nodes, and these were immunohistochemically confirmed to be of epithelial and neuroendocrine origin, consistent with MCC. Local radio‑ therapy and chemotherapy improved the symptoms; however, a change of treatment was required due to the side effects of the chemotherapy. Avelumab, an immune checkpoint inhibitor, was therefore introduced, and within a year the patient did not only experience tumor remission but also exhibited marked improvements in muscle strength and mobility. At present, 2 years later, the MCC is still in remission. To the best of our knowledge, the present report is the first to describe MCC with associated LEMS, which was successfully treated with avelumab after previous radiotherapy and chemotherapy, with both improved functional motor recovery and tumor reduc‑ tion. In conclusion, the present case report demonstrated that the present treatment strategy is a potential treatment option and could thus be considered in similar cases.

Place, publisher, year, edition, pages
Spandidos Publications, 2022
Keywords
avelumab, Lambert‑Eaton myasthenic syndrome, Merkel cell carcinoma
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-200454 (URN)10.3892/ol.2022.13513 (DOI)000891427600001 ()2-s2.0-85139567392 (Scopus ID)
Available from: 2022-10-25 Created: 2022-10-25 Last updated: 2023-09-05Bibliographically approved
Israelsson, P. (2021). Mechanisms for immune escape in epithelial ovarian cancer. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Mechanisms for immune escape in epithelial ovarian cancer
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tumors develop mechanisms to subvert the immune system, constituting immune escape. Epithelial ovarian cancer (EOC), the deadliest of all gynecological malignancies, uses a variety of mechanisms to undermine immune surveillance, aiding its establishment and metastatic spreading. Despite progress in oncoimmunology, a lot remains unknown about the cancer-immune system interplay. The aim of this thesis was to study tumor-mediated mechanisms for immune escape in EOC patients, focusing on the role of cytokines and EOC- derived exosomes. 

Cytokines are key molecules regulating immune effector functions in health and disease. We used real-time RT-qPCR and a set of primers and probes for 12 cytokines, discriminating between different immune responses and compared the cytokine mRNA expression profiles locally in the TME and systemically in peripheral blood immune cells of EOC patients, to women with benign ovarian conditions and women with normal ovaries. The cytokine mRNA expression was in general most prominent in EOC patients, confirming the immunogenicity of EOC. We found significant dominance of inflammatory and immunosuppressive/ regulatory cytokines, known to promote tumor progression by priming and activating T regulatory cell-mediated immune suppression. In contrast, IFN-γ, crucially important for evoking a cytotoxic anti-tumor response, was not upregulated. Instead, a systemic increase of IL-4 prevailed, deviating the immune defense towards humoral immunity. With regard to our cytokine study, we performed comparative analyses of cytokine mRNA versus protein expression in the EOC cell lines OVCAR-3 and SKOV-3. We found that cytokine mRNA signals were universally detected, and in some instances translated into proteins, but the protein expression levels depended on the material analyzed and the method used. Due to the high sensitivity of real-time RT-qPCR, we suggest that cytokine mRNA expression profiles can be used for some instances, such as in studies of mechanistic pathways and in comparisons between patient groups, but cannot replace expression at the protein level. 

Exosomes are nanometer-sized vesicles of endosomal origin, released by virtually all cells, participating in normal and pathological processes. Like many tumors, EOC is a great exosome producer. We isolated exosomes from EOC ascitic fluid and supernatant from tumor explant cultures to study their effect on the NK cell receptors NKG2D and DNAM-1, involved in tumor killing. We found that EOC exosomes constitutively expressed NKG2D ligands on their surface while DNAM-1 ligand expression was rare and not associated with the exosomal membrane. Consistently, the major cytotoxic pathway of NKG2D-mediated killing was dysregulated by EOC exosomes while the accessory DNAM-1- mediated pathway remained unchanged. Our results provide a mechanistic explanation to the previously made observation that in EOC patients, tumor killing is only dependent on the accessory DNAM-1 pathway. Following these iii iv results, we studied NKG2D-mediated cytotoxicity in vivo in EOC patients before and after surgery. We found that the serum exosomes isolated from EOC patients were able to downregulate the NKG2D receptor and suppress NKG2D-mediated cytotoxicity in NK cells from healthy donors, in a similar way as exosomes from EOC ascites. We also found that surgery of the primary EOC tumor has a beneficial effect on the patients’ anti-tumor cytotoxic immune response. One mechanistic explanation could be a decrease in circulating NKG2D ligand- expressing exosomes, thus improving the cytotoxic NK cell function. 

In conclusion, our results contribute to the understanding of the mechanisms responsible for tumor immune escape in general, and in EOC patients in particular, and might be useful in developing novel antitumor therapies. Our studies highlight the prevailing immunosuppression in the local TME and the immunosuppressive role of EOC exosomes. Furthermore, they support the notion that cancer surgery is also a way of removing exosome-producing cells and reducing the serum concentration of immunosuppressive exosomes, thus boosting the patients’ cytotoxic anti-tumor response. 

Abstract [sv]

Äggstockscancer är den dödligaste av alla gynekologiska cancersjukdomar. Sjukdomen ger sällan några symtom hos kvinnan förrän den har spridit sig och upptäcks således oftast sent. Därför är det viktigt att genom forskning försöka förstå mekanismerna bakom cancerns spridning och hitta markörer för tidigare diagnostik och nya sätt att behandla sjukdomen. En del av vårt immunförsvar är programmerat för att kunna känna igen och eliminera förändrade eller skadade celler, exempelvis cancerceller. Ibland utvecklar cancerceller en förmåga att nedreglera och undkomma immunförsvaret. När det sker märker inte kroppen att en tumör bildas och sprids. Syftet med denna avhandling var att studera biologiska mekanismer som ger äggstockscancer förmåga att inaktivera immunförsvaret. Äggstockscancer är nämligen en tumörtyp som har utvecklat flera mekanismer för att nedreglera kroppens immunförsvar i syfte att undvika upptäckt. Det är ännu inte helt klarlagt hur detta går till. För att försöka förstå hur äggstockscancer kan undkomma immunförsvaret har vi i detta forsknings- projekt undersökt cytokiner i tumörvävnad och exosomer som tumören utsöndrar. Cytokiner är proteiner som agerar som lösliga signalmolekyler. Exosomer är mycket små ”signalbubblor” som innehåller olika molekyler som också finns i deras modercell. Cytokiner och exosomer utsöndras av såväl kroppens friska som sjuka celler för att cellerna ska kunna kommunicera med varandra utan att vara i direkt kontakt. 

I det första delarbetet kartlades nivåerna av cytokin-mRNA, dvs. det genetiska förstadiet till cytokinproteiner, i tumörvävnad och i cirkulerande vita blodkroppar från kvinnor med äggstockscancer, och jämfördes med motsvarande uttryck hos kvinnor med godartade tillstånd i äggstockarna och kvinnor med normala äggstockar. Vi fann förhållandevis högre uttryck av cytokin-mRNA hos cancerpatienterna vilket tyder på att immunförsvaret i större utsträckning är aktiverat hos dem. Vidare dominerade nedreglerande och inflammatoriska cytokin-mRNA hos kvinnor med äggstockscancer. Cytokin-mRNA som är viktiga för vårt eget cancerförsvar och kroppens egna mördarceller visades vara nedreglerade. Mönstret sågs också i cirkulerande vita blodkroppar, vilket visar att tumören har en förmåga att påverka immunförsvaret, inte bara lokalt i tumören, utan i hela kroppen. 

I delarbete II undersökte vi sambandet mellan cytokinernas mRNA respektive proteinuttryck. Proteinet är aktivt i kroppen medan mRNA är dess genetiska förstadium. Eftersom cytokinproteiner endast uttrycks kortvarigt och lokalt samt påverkas mycket av hur ett prov tas och senare hanteras i laboratoriet, är det svårt att dra slutsatser av en proteinanalys. I en modell med odlade cancerceller jämförde vi skillnaden mellan cytokinernas mRNA- och proteinuttryck. Vi fann att metoden för proteinanalys har ett snävt spann för att kunna upptäcka protein. Om inget protein kan detekteras behöver det inte betyda att det inte finns utan provet kan behöva spädas eller koncentreras. Analys av mRNA är mindre v vi ömtåligt och har hög träffsäkerhet. Vi fann att äggstockscancerceller producerade cytokin-mRNA som kan leda till mätbara proteinnivåer. Det finns vissa fördelar med mRNA-analysen som gör att den kan användas t ex för att kartlägga en individuell cytokin mRNA-profil som kan användas vid diagnostik eller behandling. 

I delarbete III analyserades exosomer utsöndrade av äggstockscancer i form av odlade celler, vävnad, blod och ascites. Ascites är vätska i bukhålan som kvinnor med äggstockscancer kan utveckla. Vi ville undersöka om exosomer utsöndrade av cancerceller påverkar kroppens mördarceller. Vid äggstockscancer förefaller en aktiverande signalväg i mördarcellerna delvis vara utslagen. Vår hypotes var att exosomerna orsakar detta. Signalen går via något som kallas ligand- receptorsystem. En ligand är en molekyl som kan binda till en mottagarmolekyl (receptor) fäst på mördarcellernas yta. När liganden binder till receptorn får mördarcellen en signal om att den ska aktiveras och döda en målcell. Vi fann att äggstockscancer-exosomer uttrycker ligander för receptorn NKG2D på sin yta. Det är den viktigaste signalvägen i avdödandet av cancerceller. På så vis agerar exosomerna ”lockbete” och lurar mördarcellerna att nedreglera sina NKG2D- receptorer. Därmed aktiveras inte mördarcellerna för att döda cancerceller. En mindre effektiv receptor, DNAM-1, verkar istället dominera avdödande av äggstockscancerceller. Vi fann att dess ligander inte uttrycks på exosomernas yta och således lämnas denna bana opåverkad. 

Om en tumör kan opereras bort i sin helhet förbättras kvinnans prognos avseende överlevnad. I delarbete IV ville vi studera effekten av kirurgi genom att undersöka blodprover tagna före och efter operationen. Vi undersökte hur en operation påverkar mängden exosomer i blodet, de molekyler som exosomerna uttrycker och om effektiviteten hos kvinnans mördarceller påverkas. Oavsett om hela tumören opererats bort eller inte kunde vi hos samtliga patienter se en förbättrad funktion hos mördarcellerna efter operationen. En möjlig förklaring till detta är den minskade mängden exosomer i blodet som kunde observeras hos en grupp patienter efter kirurgi. Dessa kvinnor hade dessutom ett högre uttryck av NKG2D receptorn hos mördarcellerna efter operationen. 

Sammanfattningsvis har vi funnit nya mekanismer för hur äggstockscancer nedreglerar och undkommer immunförsvaret. Förhoppningsvis kan denna nya kunskap utgöra ytterligare en pusselbit i sökandet efter nya diagnostiska verktyg, nya effektiva behandlingar och i förlängningen bidra till en förbättrad överlevnad för kvinnor som drabbas av äggstockscancer. 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2021. p. 68
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2119
Keywords
human, ovarian cancer, high-grade serous cancer, EOC, HGSC, HGSOC, tumor microenvironment, immune escape, immune suppression, cytokines, exosomes, NKG2D, MICA/B, ULBP1-3, DNAM-1, surgery
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology Immunology in the medical area
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-180917 (URN)978-91-7855-484-3 (ISBN)978-91-7855-483-6 (ISBN)
Public defence
2021-03-26, Betula, målpunkt L0, plan 0, NUS, UMEÅ, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2021-03-05 Created: 2021-03-02 Last updated: 2021-03-04Bibliographically approved
Israelsson, P., Dehlin, E., Nagaev, I., Lundin, E., Ottander, U. & Mincheva-Nilsson, L. (2020). Cytokine mRNA and protein expression by cell cultures of epithelial ovarian cancer: Methodological considerations on the choice of analytical method for cytokine analyses. American Journal of Reproductive Immunology, 84(1), Article ID e13249.
Open this publication in new window or tab >>Cytokine mRNA and protein expression by cell cultures of epithelial ovarian cancer: Methodological considerations on the choice of analytical method for cytokine analyses
Show others...
2020 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 84, no 1, article id e13249Article in journal (Refereed) Published
Abstract [en]

Problem: To get a comprehensive picture of cytokine expression in health and disease is difficult, cytokines are transiently and locally expressed, and protein analyses are burdened by biological modifications, technical issues, and sensitivity to handling of samples. Thus, alternative methods, based on molecular techniques for cytokine mRNA analyses, are often used. We compared cytokine mRNA and protein expression to evaluate whether cytokine mRNA profiles can be used instead of protein analyses.

Method of study: In kinetic experiments, cytokine mRNA and protein expression of IL-1 beta, IL-6, IL-8, TNF-alpha, and TNF-beta/LTA were studied using real-time RT-qPCR and Luminex(R) microarrays in the ovarian cancer cell lines OVCAR-3, SKOV-3 and the T-cell line Jurkat, after activation of transcription by thermal stress. In addition, we analyzed IL-6 and IL-8 mRNA and protein in a small number of ovarian cancer patients.

Results: Ovarian cancer cells can express cytokines on both mRNA and protein level, with 1-4 hours' time delay between the mRNA and protein peak and a negative Spearman correlation. The mRNA and protein expression in patient samples was poorly correlated, reflecting previous studies.

Conclusion: Cytokine mRNA and protein expression levels show diverging results, depending on the material analyzed and the method used. Considering the high sensitivity and reproducibility of real-time RT-qPCR, we suggest that cytokine mRNA profiles could be used as a proxy for protein expression for some specific purposes, such as comparisons between different patient groups, and in defining mechanistic pathways involved in the pathogenesis of cancer and other pathological conditions.

Place, publisher, year, edition, pages
John Wiley & Sons, 2020
Keywords
cytokine, mRNA, ovarian cancer, protein, protein microarray, real-time polymerase chain reaction
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-171392 (URN)10.1111/aji.13249 (DOI)000530699700001 ()32307767 (PubMedID)2-s2.0-85085074930 (Scopus ID)
Available from: 2020-06-12 Created: 2020-06-12 Last updated: 2023-03-24Bibliographically approved
Israelsson, P., Labani-Motlagh, A., Nagaev, I., Dehlin, E., Nagaeva, O., Lundin, E., . . . Mincheva-Nilsson, L. (2019). Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary. International Journal of Gynecological Cancer, 29, A138-A138
Open this publication in new window or tab >>Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary
Show others...
2019 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 29, p. A138-A138Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction/Background 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.

Methodology 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.

Conclusion 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.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-170021 (URN)10.1136/ijgc-2019-ESGO.191 (DOI)000523502500191 ()
Note

Supplement: 4

Meeting Abstract: P129

Available from: 2020-05-05 Created: 2020-05-05 Last updated: 2020-05-05Bibliographically approved
Israelsson, P., Labani-Motlagh, A., Nagaev, I., Dehlin, E., Nagaeva, O., Lundin, E., . . . Mincheva-Nilsson, L. (2017). Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary. Journal of Cancer Science & Therapy, 9(5), 422-429
Open this publication in new window or tab >>Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary
Show others...
2017 (English)In: Journal of Cancer Science & Therapy, ISSN 1948-5956, Vol. 9, no 5, p. 422-429Article in journal (Refereed) 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.

Keywords
Cytokines, High-grade serous ovarian carcinoma (HGSC), EOC, Tumor microenvironment, Tumor inflammation, Immune suppression
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-138256 (URN)10.4172/1948-5956.1000453 (DOI)
Available from: 2017-08-15 Created: 2017-08-15 Last updated: 2021-03-02Bibliographically approved
Labani-Motlagh, A., Israelsson, P., Ottander, U., Lundin, E., Nagaev, I., Nagaeva, O., . . . Mincheva-Nilsson, L. (2016). Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity. Tumor Biology, 37(4), 5455-5466
Open this publication in new window or tab >>Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity
Show others...
2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 4, p. 5455-5466Article in journal (Refereed) 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.

Keywords
Epithelial ovarian cancer/EOC, Tumor, Exosomes, NKG2D, DNAM-1/CD266, Cytotoxicity, MICA/B, ULBP, PVR, Nectin-2
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-118529 (URN)10.1007/s13277-015-4313-2 (DOI)000374904500128 ()26563374 (PubMedID)2-s2.0-84946924480 (Scopus ID)
Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2023-03-23Bibliographically approved
Israelsson, P., Oda, H., Öfverman, C., Stefansson, K. & Lindquist, D.High LMO-7 expression is a positive prognostic factor in oropharyngeal squamous cell carcinoma.
Open this publication in new window or tab >>High LMO-7 expression is a positive prognostic factor in oropharyngeal squamous cell carcinoma
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-214807 (URN)
Available from: 2023-09-30 Created: 2023-09-30 Last updated: 2023-10-04
Israelsson, P., Björk, E., Nagaev, I., Nagaeva, O., Lundin, E., Mincheva-Nilsson, L. & Ottander, U.The influence of surgery on circulating ovarian cancer exosomes and the NKG2D‐mediated cytotoxicity.
Open this publication in new window or tab >>The influence of surgery on circulating ovarian cancer exosomes and the NKG2D‐mediated cytotoxicity
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-180914 (URN)
Available from: 2021-03-02 Created: 2021-03-02 Last updated: 2021-03-02
Organisations

Search in DiVA

Show all publications