Browsing by Subject "tumor microenvironment"

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  • Cervera-Carrascon, Victor; Quixabeira, Dafne C. A.; Santos, Joao M.; Havunen, Riikka; Milenova, Ioanna; Verhoeff, Jan; Heinio, Camilla; Zafar, Sadia; Garcia-Vallejo, Juan J.; van Beusechem, Victor W.; de Gruijl, Tanja D.; Kalervo, Aino; Sorsa, Suvi; Kanerva, Anna; Hemminki, Akseli (2021)
    Immune checkpoint inhibitors such as anti-PD-1 have revolutionized the field of oncology over the past decade. Nevertheless, the majority of patients do not benefit from them. Virotherapy is a flexible tool that can be used to stimulate and/or recruit different immune populations. T-cell enabling virotherapy could enhance the efficacy of immune checkpoint inhibitors, even in tumors resistant to these inhibitors. The T-cell potentiating virotherapy used here consisted of adenoviruses engineered to express tumor necrosis factor alpha and interleukin-2 in the tumor microenvironment. To study virus efficacy in checkpoint-inhibitor resistant tumors, we developed an anti-PD-1 resistant melanoma model in vivo. In resistant tumors, adding virotherapy to an anti-PD-1 regimen resulted in increased survival (p=0.0009), when compared to anti-PD-1 monotherapy. Some of the animals receiving virotherapy displayed complete responses, which did not occur in the immune checkpoint-inhibitor monotherapy group. When adenoviruses were delivered into resistant tumors, there were signs of increased CD8 T-cell infiltration and activation, which - together with a reduced presence of M2 macrophages and myeloid-derived suppressor cells - could explain those results. T-cell enabling virotherapy appeared as a valuable tool to counter resistance to immune checkpoint inhibitors. The clinical translation of this approach could increase the number of cancer patients benefiting from immunotherapies.
  • Gonzalez, Marta Lopez; Oosterhoff, Dinja; Lindenberg, Jelle J.; Milenova, Ioanna; Lougheed, Sinead M.; Martianez, Tania; Dekker, Henk; Quixabeira, Dafne Carolina Alves; Hangalapura, Basav; Joore, Jos; Piersma, Sander R.; Cervera-Carrascon, Victor; Santos, Joao Manuel; Scheper, Rik J.; Verheul, Henk M. W.; Jimenez, Connie R.; Van De Ven, Rieneke; Hemminki, Akseli; Van Beusechem, Victor W.; De Gruijl, Tanja D. (2019)
    In patients with cancer, the functionality of Dendritic Cells (DC) is hampered by high levels of tumor-derived suppressive cytokines, which interfere with DC development and maturation. Poor DC development can limit the efficacy of immune checkpoint blockade and in vivo vaccination approaches. Interference in intracellular signaling cascades downstream from the receptors of major tumor-associated suppressive cytokines like IL-10 and IL-6, might improve DC development and activation, and thus enhance immunotherapy efficacy. We performed exploratory functional screens on arrays consisting of >1000 human kinase peptide substrates to identify pathways involved in DC development and its inhibition by IL-10 or IL-6. The resulting alterations in phosphorylation of the kinome substrate profile pointed to glycogen-synthase kinase-3 beta (GSK3 beta) as a pivotal kinase in both DC development and suppression. GSK3 beta inhibition blocked human DC differentiation in vitro, which was accompanied by decreased levels of IL-12p70 secretion, and a reduced capacity for T cell priming. More importantly, adenoviral transduction of monocytes with a constitutively active form of GSK3 beta induced resistance to the suppressive effects of IL-10 and melanoma-derived supernatants alike, resulting in improved DC development, accompanied by up-regulation of co-stimulatory markers, an increase in CD83 expression levels in mature DC, and diminished release of IL-10. Moreover, adenovirus-mediated intratumoral manipulation of this pathway in an in vivo melanoma model resulted in DC activation and recruitment, and in improved immune surveillance and tumor control. We propose the induction of constitutive GSK3 beta activity as a novel therapeutic means to bolster DC functionality in the tumor microenvironment.
  • Perut, Francesca; Tasso, Roberta; Mannerström, Bettina (2022)
  • Belitskin, Denis; Pant, Shishir M.; Munne, Pauliina; Suleymanova, Ilida; Belitskina, Kati; Ala-Hongisto, Hanna; Englund, Johanna; Raatikainen, Tiina; Klezovitch, Olga; Vasioukhin, Valeri; Li, Shuo; Wu, Qingyu; Monni, Outi; Kuure, Satu; Laakkonen, Pirjo; Pouwels, Jeroen; Tervonen, Topi A.; Klefström, Juha (2021)
    Transforming growth factor-beta (TGF beta) is a multifunctional cytokine with a well-established role in mammary gland development and both oncogenic and tumor-suppressive functions. The extracellular matrix (ECM) indirectly regulates TGF beta activity by acting as a storage compartment of latent-TGF beta, but how TGF beta is released from the ECM via proteolytic mechanisms remains largely unknown. In this study, we demonstrate that hepsin, a type II transmembrane protease overexpressed in 70% of breast tumors, promotes canonical TGF beta signaling through the release of latent-TGF beta from the ECM storage compartment. Mammary glands in hepsin CRISPR knockout mice showed reduced TGF beta signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent-TGF beta 1, while overexpression of hepsin in mammary tumors increased TGF beta signaling. Cell-free and cell-based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent-TGF beta and, importantly, that the ability of hepsin to activate TGF beta signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGF beta pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin.
  • Turunen, S. Pauliina; Tatti-Bugaeva, Olga; Lehti, Kaisa (2017)
    Membrane-type matrix metalloproteases (MT-MMP) are pivotal regulators of cell invasion, growth and survival. Tethered to the cell membranes by a transmembrane domain or GPI-anchor, the six MT-MMPs can exert these functions via cell surface-associated extracellular matrix degradation or proteolytic protein processing, including shedding or release of signaling receptors, adhesion molecules, growth factors and other pericellular proteins. By interactions with signaling scaffold or cytoskeleton, the C-terminal cytoplasmic tail of the transmembrane MT-MMPs further extends their functionality to signaling or structural relay. MT-MMPs are differentially expressed in cancer. The most extensively studied MMP14/MT1-MMP is induced in various cancers along malignant transformation via pathways activated by mutations in tumor suppressors or proto-oncogenes and changes in tumor microenvironment including cellular heterogeneity, extracellular matrix composition, tissue oxygenation, and inflammation. Classically such induction involves transcriptional programs related to epithelial-to-mesenchymal transition. Besides inhibition by endogenous tissue inhibitors, MT-MMP activities are spatially and timely regulated at multiple levels by microtubular vesicular trafficking, dimerization/oligomerization, other interactions and localization in the actin-based invadosomes, in both tumor and the stroma. The functions of MT-MMPs are multifaceted within reciprocal cellular responses in the evolving tumor microenvironment, which poses the importance of these proteases beyond the central function as matrix scissors, and necessitates us to rethink MT-MMPs as dynamic signaling proteases of cancer. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
  • Gonzalez-Molina, Jordi; Gramolelli, Silvia; Liao, Zehuan; Carlson, Joseph W.; Ojala, Päivi M.; Lehti, Kaisa (2019)
    Sarcomas are deadly malignant tumors of mesenchymal origin occurring at all ages. The expression and function of the membrane-type matrix metalloproteinase MMP14 is closely related to the mesenchymal cell phenotype, and it is highly expressed in most sarcomas. MMP14 regulates the activity of multiple extracellular and plasma membrane proteins, influencing cell-cell and cell-extracellular matrix (ECM) communication. This regulation mediates processes such as ECM degradation and remodeling, cell invasion, and cancer metastasis. Thus, a comprehensive understanding of the biology of MMP14 in sarcomas will shed light on the mechanisms controlling the key processes in these diseases. Here, we provide an overview of the function and regulation of MMP14 and we discuss their relationship with clinical and pre-clinical MMP14 data in both adult and childhood sarcomas.
  • Santos, João Manuel; Heiniö, Camilla; Cervera-Carrascon, Victor; Quixabeira, Dafne C A; Siurala, Mikko; Havunen, Riikka; Butzow, Ralf; Zafar, Sadia; de Gruijl, Tanja; Lassus, Heini; Kanerva, Anna; Hemminki, Akseli (2020)
    BACKGROUND: Ovarian cancers often contain significant numbers of tumor-infiltrating lymphocytes (TILs) that can be readily harnessed for adoptive T-cell therapy (ACT). However, the immunosuppressive ovarian tumor microenvironment and lack of tumor reactivity in TILs can limit the effectiveness of the therapy. We hypothesized that by using an oncolytic adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) to deliver tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2), we could counteract immunosuppression, and enhance antitumor TIL responses in ovarian cancer (OVCA). METHODS: We established ex vivo tumor cultures freshly derived from patients with advanced OVCA and evaluated the effects of Ad5/3-E2F-D24-hTNFa-IRES-hIL2 or Ad5/3-E2F-D24 (the control virus without TNFa and IL-2) on TILs, cytokine response and tumor viability. Tumor reactivity was assessed by determining interferon gamma (IFNg) response of clinically relevant TILs towards autologous T-cell-depleted ex vivo tumor cultures pretreated with or without the aforementioned oncolytic adenoviruses. RESULTS: Treatment of ex vivo tumor cultures with Ad5/3-E2F-D24-hTNFa-IRES-hIL2 caused a substantial rise in proinflammatory signals: increased secretion of IFNg, CXCL10, TNFa and IL-2, and concomitant activation of CD4+ and CD8+ TILs. Potent tumor reactivity was seen, as clinically relevant TIL secreted high levels of IFNg in response to autologous T-cell-depleted ovarian ex vivo tumor cultures treated with Ad5/3-E2F-D24-hTNFa-IRES-hIL2. This phenomenon was independent of PD-L1 expression in tumor cells, a factor that determined the variability of IFNg responses seen in different patient samples. CONCLUSIONS: Overall, oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 was able to rewire the ovarian tumor microenvironment to accommodate heightened antitumor TIL reactivity. Such effects may improve the clinical effectiveness of ACT with TILs in patients with advanced OVCA.
  • Zafar, Sadia; Basnet, Saru; Launonen, Inga-Maria; Quixabeira, Dafne Carolina Alves; Santos, Joao; Hemminki, Otto; Malmstedt, Minna; Cervera-Carrascon, Victor; Aronen, Pasi; Kalliokoski, Riikka; Havunen, Riikka; Rannikko, Antti; Mirtti, Tuomas; Matikainen, Mika; Kanerva, Anna; Hemminki, Akseli (2021)
    Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.
  • Karihtala, Kristiina; Leivonen, Suvi-Katri; Brück, Oscar; Karjalainen-Lindsberg, Marja-Liisa; Mustjoki, Satu; Pellinen, Teijo; Leppä, Sirpa (2020)
    Tumor microenvironment and immune escape affect pathogenesis and survival in classical Hodgkin lymphoma (cHL). While tumor-associated macrophage (TAM) content has been associated with poor outcomes, macrophage-derived determinants with clinical impact have remained undefined. Here, we have used multiplex immunohistochemistry and digital image analysis to characterize TAM immunophenotypes with regard to expression of checkpoint molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO-1) from the diagnostic tumor tissue samples of 130 cHL patients, and correlated the findings with clinical characteristics and survival. We show that a large proportion of TAMs express PD-L1 (CD68(+), median 32%; M2 type CD163(+), median 22%), whereas the proportion of TAMs expressing IDO-1 is lower (CD68(+), median 5.5%; CD163(+), median 1.4%). A high proportion of PD-L1 and IDO-1 expressing TAMs from all TAMs (CD68(+)), or from CD163(+) TAMs, is associated with inferior outcome. In multivariate analysis with age and stage, high proportions of PD-L1(+) and IDO-1(+) TAMs remain independent prognostic factors for freedom from treatment failure (PD-L1(+)CD68(+)/CD68(+), HR = 2.63, 95% CI 1.17-5.88, p = 0.019; IDO-1(+)CD68(+)/CD68(+), HR = 2.48, 95% CI 1.03-5.95, p = 0.042). In contrast, proportions of PD-L1(+) tumor cells, all TAMs or PD-L1(-) and IDO-1(-) TAMs are not associated with outcome. The findings implicate that adverse prognostic impact of TAMs is checkpoint-dependent in cHL.
  • Saba, Nabil F.; Vijayvargiya, Pooja; Vermorken, Jan B.; Rodrigo, Juan P.; Willems, Stefan M.; Zidar, Nina; de Bree, Remco; Mäkitie, Antti; Wolf, Greg T.; Argiris, Athanassios; Teng, Yong; Ferlito, Alfio (2022)
    Simple Summary Therapies for squamous cell carcinomas of the head and neck (SCCHN) have been rapidly evolving, initially with the inclusion of immunotherapy, but more recently with the consideration of anti-angiogenic therapies. Recent preclinical and clinical data reveal a strong correlation between vascular endothelial growth factor (VEGF) and the progression of SCCHN, with nearly 90% of these malignancies expressing VEGF. Our review article not only elaborates on the utility of anti-VEGF therapies on SCCHN but also its interaction with the immune environment. Furthermore, we detailed the current data on immunotherapies targeting SCCHN and how this could be coupled with anti-angiogenics therapies. Despite the lack of approved anti-angiogenic therapies in squamous cell carcinoma of the head and neck (SCCHN), preclinical and more recent clinical evidence support the role of targeting the vascular endothelial growth factor (VEGF) in this disease. Targeting VEGF has gained even greater interest following the recent evidence supporting the role of immunotherapy in the management of advanced SCCHN. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of SCCHN, and clinical evidence exists as to the value of combining this strategy with immunotherapeutic agents. Close to 90% of SCCHNs express VEGF, which has been correlated with a worse clinical prognosis and an increased resistance to chemotherapeutic agents. As immunotherapy is currently at the forefront of the management of advanced SCCHN, revisiting the rationale for targeting angiogenesis in this disease has become an even more attractive proposition.
  • Rasheed, Kashif; Moens, Ugo; Policastro, Benedetta; Johnsen, John Inge; Koljonen, Virve; Sihto, Harri; Lui, Weng-Onn; Sveinbjørnsson, Baldur (2022)
    Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients.