{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T13:02:45Z","timestamp":1789909365500,"version":"4.0.1"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,3,26]],"date-time":"2020-03-26T00:00:00Z","timestamp":1585180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In order to break tumor resistance towards traditional treatments, we investigate the response of tumor and immune cells to a novel, cytokine-armed oncolytic adenovirus: Ad5\/3-d24-E2F-hTNFa-IRES-hIL2 (also known as TILT-123 and OAd.TNFa-IL2). There are several pattern recognition receptors (PRR) that might mediate adenovirus-infection recognition. However, the role and specific effects of each PRR on the tumor microenvironment and treatment outcome remain unclear. Hence, the aim of this study was to investigate the effects of OAd.TNFa-IL2 infection on PRR-mediated danger- and pathogen-associated molecular pattern (DAMP and PAMP, respectively) signaling. In addition, we wanted to see which PRRs mediate an antitumor response and are therefore relevant for optimizing this virotherapy. We determined that OAd.TNFa-IL2 induced DAMP and PAMP release and consequent tumor microenvironment modulation. We show that the AIM2 inflammasome is activated during OAd.TNFa-IL2 virotherapy, thus creating an immunostimulatory antitumor microenvironment.<\/jats:p>","DOI":"10.3390\/cells9040798","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T05:52:30Z","timestamp":1585720350000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["TNFa and IL2 Encoding Oncolytic Adenovirus Activates Pathogen and Danger-Associated Immunological Signaling"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-2146","authenticated-orcid":false,"given":"Camilla","family":"Heini\u00f6","sequence":"first","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, TRIMM, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riikka","family":"Havunen","sequence":"additional","affiliation":[{"name":"TILT Biotherapeutics Ltd., Haartmaninkatu 3, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao","family":"Santos","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, TRIMM, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., Haartmaninkatu 3, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaas","family":"de Lint","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Department of Clinical Genetics, Section Oncogenetics, Amsterdam UMC, De Boelelaan 1117, 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6684-3666","authenticated-orcid":false,"given":"Victor","family":"Cervera-Carrascon","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, TRIMM, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., Haartmaninkatu 3, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kanerva","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, TRIMM, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland"},{"name":"Department of Obstetrics and Gynecology, Helsinki University Hospital, Haartmaninkatu 2, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akseli","family":"Hemminki","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, TRIMM, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., Haartmaninkatu 3, 00290 Helsinki, Finland"},{"name":"Helsinki University Hospital Comprehensive Cancer Center, Paciuksenkatu 3, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1200\/EDBK_237987","article-title":"Reprogramming the Tumor Microenvironment to Improve Immunotherapy: Emerging Strategies and Combination Therapies","volume":"39","author":"Datta","year":"2019","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1089\/hum.2018.240","article-title":"Effect of Genetic Modifications on Physical and Functional Titers of Adenoviral Cancer Gene Therapy Constructs","volume":"30","author":"Sorsa","year":"2019","journal-title":"Hum. Gene. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1177\/1060028017702654","article-title":"Talimogene Laherparepvec: An Oncolytic Virus Therapy for Melanoma","volume":"51","author":"Corrigan","year":"2017","journal-title":"Ann. Pharmacother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1200\/JCO.2014.58.3377","article-title":"Talimogene Laherparepvec Improves Durable Response Rate in Patients with Advanced Melanoma","volume":"33","author":"Andtbacka","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.omto.2016.12.004","article-title":"Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy","volume":"4","author":"Havunen","year":"2017","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18538","DOI":"10.1073\/pnas.0509182102","article-title":"Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+\/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer","volume":"102","author":"Sato","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1093\/annonc\/mdv239","article-title":"Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials","volume":"26","author":"Dieci","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1158\/1535-7163.MCT-05-0310","article-title":"AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model","volume":"5","author":"Chen","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4932","DOI":"10.7150\/jca.32806","article-title":"STING signaling is a potential immunotherapeutic target in colorectal cancer","volume":"10","author":"Chon","year":"2019","journal-title":"J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"811","DOI":"10.2147\/OTT.S125039","article-title":"AIM2 regulates viability and apoptosis in human colorectal cancer cells via the PI3K\/Akt pathway","volume":"10","author":"Chen","year":"2017","journal-title":"Onco Targets Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Xiao, X., Yang, G., Bai, P., Gui, S., Nyuyen, T.M., Mercado-Uribe, I., Yang, M., Zou, J., Li, Q., and Xiao, J. (2016). Inhibition of nuclear factor-kappa B enhances the tumor growth of ovarian cancer cell line derived from a low-grade papillary serous carcinoma in p53-independent pathway. 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Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/eji.201545839","article-title":"AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity","volume":"46","author":"Man","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.jaad.2014.06.012","article-title":"Absent in Melanoma 2 is predominantly present in primary melanoma and primary squamous cell carcinoma, but largely absent in metastases of both tumors","volume":"71","author":"Zeeuwen","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/ijc.23074","article-title":"Modulation of viability and maturation of human monocyte-derived dendritic cells by oncolytic adenoviruses","volume":"122","author":"Schierer","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23888","DOI":"10.1074\/jbc.M202937200","article-title":"Myotrophin\/V-1, a protein up-regulated in the failing human heart and in postnatal cerebellum, converts NFkappa B p50-p65 heterodimers to p50-p50 and p65-p65 homodimers","volume":"277","author":"Knuefermann","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1038\/mt.2016.137","article-title":"Adenoviral Delivery of Tumor Necrosis Factor-\u03b1 and Interleukin-2 Enables Successful Adoptive Cell Therapy of Immunosuppressive Melanoma","volume":"24","author":"Siurala","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1002\/ijc.26339","article-title":"Calreticulin promotes tumor lymphocyte infiltration and enhances the antitumor effects of immunotherapy by up-regulating the endothelial expression of adhesion molecules","volume":"130","author":"Wang","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_22","first-page":"422","article-title":"DAMPs from Cell Death to New Life","volume":"6","author":"Ceriotti","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1172\/JCI62423","article-title":"Alarmins: Awaiting a clinical response","volume":"122","author":"Chan","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Krysko, O., L\u00f8ve Aaes, T., Bachert, C., Vandenabeele, P., and Krysko, D.V. (2013). Many faces of DAMPs in cancer therapy. Cell Death Dis., 4.","DOI":"10.1038\/cddis.2013.156"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.4049\/jimmunol.166.3.1611","article-title":"Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses","volume":"166","author":"Ferrari","year":"2001","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/sj.mt.6300031","article-title":"Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors","volume":"15","author":"Cerullo","year":"2007","journal-title":"Mol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1189\/jlb.1012501","article-title":"TLR agonists: Our best frenemy in cancer immunotherapy","volume":"93","author":"Kaczanowska","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1476-4598-12-26","article-title":"IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus","volume":"12","author":"Chen","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nish, S.A., Schenten, D., Wunderlich, F.T., Pope, S.D., Gao, Y., Hoshi, N., Yu, S., Yan, X., Lee, H.K., and Pasman, L. (2014). T cell-intrinsic role of IL-6 signaling in primary and memory responses. eLife, 3.","DOI":"10.7554\/eLife.01949"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-immunol-042617-053352","article-title":"Signaling and Function of Interleukin-2 in T Lymphocytes","volume":"36","author":"Ross","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1615\/CritRevEukarGeneExpr.v20.i2.10","article-title":"Tumor necrosis factor-\u03b1 signaling in macrophages","volume":"20","author":"Parameswaran","year":"2010","journal-title":"Crit. Rev. Eukaryot. Gene Expr."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/4\/798\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:11:57Z","timestamp":1760173917000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/4\/798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,26]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["cells9040798"],"URL":"https:\/\/doi.org\/10.3390\/cells9040798","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,26]]}}}