TY - JOUR A1 - Schäfer, Sarah A1 - Zernecke, Alma T1 - CD8\(^+\) T cells in atherosclerosis JF - Cells N2 - Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8\(^+\) T cells. The CD8\(^+\) T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8\(^+\) T cells ameliorates atherosclerosis. CD8\(^+\) T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8\(^+\) T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8\(^+\) T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8\(^+\) T cells and their cytotoxic activity. CD8\(^+\) T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25\(^+\)CD8\(^+\) T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8\(^+\) T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8\(^+\) T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8\(^+\) T cells in atherosclerosis. KW - atherosclerosis KW - CD8\(^+\) T cells KW - inflammation KW - cytotoxic T cells KW - single cell RNA sequencing KW - checkpoint inhibitors KW - immunotherapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220170 SN - 2073-4409 VL - 10 IS - 1 ER - TY - JOUR A1 - Pellegrino, Marsha A1 - Del Bufalo, Francesca A1 - De Angelis, Biagio A1 - Quintarelli, Concetta A1 - Caruana, Ignazio A1 - de Billy, Emmanuel T1 - Manipulating the metabolism to improve the efficacy of CAR T-cell immunotherapy JF - Cells N2 - The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products. KW - cancer KW - metabolic reprogramming KW - combined therapy KW - Chimeric Antigen Receptor T cells KW - immunotherapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220140 SN - 2073-4409 VL - 10 IS - 1 ER - TY - JOUR A1 - Landwehr, Laura-Sophie A1 - Altieri, Barbara A1 - Schreiner, Jochen A1 - Sbiera, Iuliu A1 - Weigand, Isabel A1 - Kroiss, Matthias A1 - Fassnacht, Martin A1 - Sbiera, Silviu T1 - Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma JF - Journal for ImmunoTherapy of Cancer N2 - Background Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in similar to 60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy. Methods We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3\(^+\)), T helper cells (CD3\(^+\)CD4\(^+\)), cytotoxic T cells (CD3\(^+\)CD8\(^+\)) and regulatory T cells (Tregs; CD3\(^+\)CD4\(^+\)FoxP3\(^+\)) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess). Results 86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4\(^+\)- and CD8\(^+\) subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess). Conclusion Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies. KW - immunity KW - immunotherapy KW - lymphocytes KW - tumor-infiltrating KW - t-lymphocytes KW - tumor microenvironment Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229893 VL - 8 ER - TY - JOUR A1 - Henke, Erik A1 - Nandigama, Rajender A1 - Ergün, Süleyman T1 - Extracellular matrix in the tumor microenvironment and its impact on cancer therapy JF - Frontiers in Molecular Biosciences N2 - Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy. KW - extracellular matrix KW - cancer therapy KW - drug transport KW - immunotherapy KW - chemotherapy (CH) KW - radiotherapy KW - tumor microenvironment KW - ECM Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199341 SN - 2296-889X VL - 6 IS - 160 ER -