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  • 1
    Online Resource
    Online Resource
    Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 12 ( 2020-11-30), p. 3586-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 12 ( 2020-11-30), p. 3586-
    Abstract: The type I cytokine family members interleukin-2 (IL-2) and IL-15 play important roles in the homeostasis of innate and adaptive immunity. Although IL-2 and IL-15 receptor complexes activate similar signal transduction cascades, triggering of these receptors results in different functional activities in lymphocytes. While IL-2 expands regulatory T cells and CD4+ helper T cells, IL-15 supports the development of central memory T cells and NK cells. Recent data have provided evidence that IL-2 and IL-15 differ in their ability to activate T and NK cells to resist various forms of immune suppression. The diverse roles of these two cytokines have on immune cells lead to critical therapeutic implications for cancer treatment. In this review, we discuss the distinct roles of IL-2 and IL-15 in activating various functions in T and NK cells with a particular focus on the signals that participate in the resistance of tumor-derived immune suppressive factors. Furthermore, we summarize current clinical applications of IL-2 and IL-15 in metastatic malignancies, either as monotherapy or in combination with other agents, and highlight the future trends for research on these cytokine-based immunotherapies.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12123586
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System
    MDPI AG ; 2014
    In:  International Journal of Molecular Sciences Vol. 15, No. 10 ( 2014-10-14), p. 18557-18573
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 15, No. 10 ( 2014-10-14), p. 18557-18573
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms151018557
    Language: English
    Publisher: MDPI AG
    Publication Date: 2014
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Deciphering the Role of p60AmotL2 in Epithelial Extrusion and Cell Detachment
    MDPI AG ; 2023
    In:  Cells Vol. 12, No. 17 ( 2023-08-28), p. 2158-
    Details
    In: Cells, MDPI AG, Vol. 12, No. 17 ( 2023-08-28), p. 2158-
    Abstract: Preserving an accurate cell count is crucial for maintaining homeostasis. Apical extrusion, a process in which redundant cells are eliminated by neighboring cells, plays a key role in this regard. Recent studies have revealed that apical extrusion can also be triggered in cells transformed by oncogenes, suggesting it may be a mechanism through which tumor cells escape their microenvironment. In previous work, we demonstrated that p60AmotL2 modulates the E-cadherin function by inhibiting its connection to radial actin filaments. This isoform of AmotL2 is expressed in invasive breast and colon tumors and promotes invasion in vitro and in vivo. Transcriptionally regulated by c-Fos, p60AmotL2 is induced by local stress signals such as severe hypoxia. In this study, we investigated the normal role of p60AmotL2 in epithelial tissues. We found that this isoform is predominantly expressed in the gut, where cells experience rapid turnover. Through time-lapse imaging, we present evidence that cells expressing p60AmotL2 are extruded by their normal neighboring cells. Based on these findings, we hypothesize that tumor cells exploit this pathway to detach from normal epithelia and invade surrounding tissues.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells12172158
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2661518-6
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  • 4
    Online Resource
    Online Resource
    Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 2 ( 2021-02-09), p. 353-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 2 ( 2021-02-09), p. 353-
    Abstract: CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137—CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137—CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10020353
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2661518-6
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  • 5
    Online Resource
    Online Resource
    CD11c-CD8 Spatial Cross Presentation: A Novel Approach to Link Immune Surveillance and Patient Survival in Soft Tissue Sarcoma
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 5 ( 2021-03-09), p. 1175-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 5 ( 2021-03-09), p. 1175-
    Abstract: Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13051175
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 6
    Online Resource
    Online Resource
    Strategies to Augment Natural Killer (NK) Cell Activity against Solid Tumors
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 7 ( 2019-07-23), p. 1040-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 7 ( 2019-07-23), p. 1040-
    Abstract: The immune system plays a crucial role to prevent local growth and dissemination of cancer. Therapies based on activating the immune system can result in beneficial responses in patients with metastatic disease. Treatment with antibodies targeting the immunological checkpoint axis PD-1 / PD-L1 can result in the induction of anti-tumor T cell activation leading to meaningful long-lasting clinical responses. Still, many patients acquire resistance or develop dose-limiting toxicities to these therapies. Analysis of tumors from patients who progress on anti-PD-1 treatment reveal defective interferon-signaling and antigen presentation, resulting in immune escape from T cell-mediated attack. Natural killer (NK) cells are innate lymphocytes that can kill tumor cells without prior sensitization to antigens and can be activated to kill tumor cells that have an impaired antigen processing and presentation machinery. Thus, NK cells may serve as useful effectors against tumor cells that have become resistant to classical immune checkpoint therapy. Various approaches to activate NK cells are being increasingly explored in clinical trials against cancer. While clinical benefit has been demonstrated in patients with acute myeloid leukemia receiving haploidentical NK cells, responses in patients with solid tumors are so far less encouraging. Several hurdles need to be overcome to provide meaningful clinical responses in patients with solid tumors. Here we review the recent developments to augment NK cell responses against solid tumors with regards to cytokine therapy, adoptive infusion of NK cells, NK cell engagers, and NK cell immune checkpoints.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11071040
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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