TY - JOUR A1 - Romero‐Olmedo, Addi J. A1 - Schulz, Axel R. A1 - Huber, Magdalena A1 - Brehm, Corinna U. A1 - Chang, Hyun‐Dong A1 - Chiarolla, Cristina M. A1 - Bopp, Tobias A1 - Skevaki, Chrysanthi A1 - Berberich‐Siebelt, Friederike A1 - Radbruch, Andreas A1 - Mei, Henrik E. A1 - Lohoff, Michael T1 - Deep phenotypical characterization of human CD3\(^{+}\)CD56\(^{+}\) T cells by mass cytometry JF - European Journal of Immunology N2 - CD56\(^{+}\) T cells are a group of pro‐inflammatory CD3\(^{+}\) lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3\(^{+}\)CD56\(^{+}\) cells in peripheral blood of normal human donors and individuals sensitized to birch‐pollen or/and house dust mite by high‐dimensional mass cytometry combined with manual and computational data analysis. A co‐regulation between major conventional T‐cell subsets and their respective CD3\(^{+}\)CD56\(^{+}\) cell counterparts appeared restricted to CD8\(^{+}\), MAIT, and TCRγδ\(^{+}\) T‐cell compartments. Interestingly, we find a co‐regulation of several CD3\(^{+}\)CD56\(^{+}\) cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56\(^{+}\) T‐cell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3\(^{+}\)CD56\(^{+}\) subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3\(^{+}\)CD56\(^{+}\) FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions. KW - allergy KW - CD56 KW - human KW - mass cytometry KW - T cells Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225699 VL - 51 IS - 3 SP - 672 EP - 681 ER - TY - JOUR A1 - Weich, Alexander A1 - Werner, Rudolf A. A1 - Buck, Andreas K. A1 - Hartrampf, Philipp E. A1 - Serfling, Sebastian E. A1 - Scheurlen, Michael A1 - Wester, Hans-Jürgen A1 - Meining, Alexander A1 - Kircher, Stefan A1 - Higuchi, Takahiro A1 - Pomper, Martin G. A1 - Rowe, Steven P. A1 - Lapa, Constantin A1 - Kircher, Malte T1 - CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas JF - Diagnostics N2 - We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer \(^{68}\)Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard \(^{18}\)F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent \(^{18}\)F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. \(^{68}\)Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while \(^{18}\)F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, \(^{18}\)F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to \(^{68}\)Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard \(^{18}\)F-FDG PET/CT. KW - CXCR4 KW - NET KW - NEC KW - 68Ga-Pentixafor KW - 18F-FDG Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234231 SN - 2075-4418 VL - 11 IS - 4 ER - TY - JOUR A1 - Rosenfeldt, Mathias T. A1 - Hartmann, Elena M. A1 - Leng, Corinna A1 - Rosenwald, Andreas A1 - Anagnostopoulos, Ioannis T1 - A case of nodular lymphocyte predominant Hodgkin lymphoma with unexpected EBV-latency type JF - Annals of Hematology N2 - No abstract available. KW - nodular lymphcyte KW - Hodgkin lymphoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232571 SN - 0939-5555 VL - 100 ER - TY - JOUR A1 - Upcin, Berin A1 - Henke, Erik A1 - Kleefeldt, Florian A1 - Hoffmann, Helene A1 - Rosenwald, Andreas A1 - Irmak-Sav, Ster A1 - Aktas, Huseyin Bertal A1 - Rückschloß, Uwe A1 - Ergün, Süleyman T1 - Contribution of adventitia-derived stem and progenitor cells to new vessel formation in tumors JF - Cells N2 - Blocking tumor vascularization has not yet come to fruition to the extent it was hoped for, as angiogenesis inhibitors have shown only partial success in the clinic. We hypothesized that under- appreciated vascular wall-resident stem and progenitor cells (VW-SPCs) might be involved in tumor vascularization and influence effectiveness of anti-angiogenic therapy. Indeed, in patient samples, we observed that vascular adventitia-resident CD34\(^+\) VW-SPCs are recruited to tumors in situ from co-opted vessels. To elucidate this in detail, we established an ex vivo model using concomitant embedding of multi-cellular tumor spheroids (MCTS) and mouse aortic rings (ARs) into collagen gels, similar to the so-called aortic ring assay (ARA). Moreover, ARA was modified by removing the ARs’ adventitia that harbors VW-SPCs. Thus, this model enabled distinguishing the contribution of VW-SPCs from that of mature endothelial cells (ECs) to new vessel formation. Our results show that the formation of capillary-like sprouts is considerably delayed, and their number and network formation were significantly reduced by removing the adventitia. Substituting iPSC-derived neural spheroids for MCTS resulted in distinct sprouting patterns that were also strongly influenced by the presence or absence of VW-SPCs, also underlying the involvement of these cells in non-pathological vascularization. Our data suggest that more comprehensive approaches are needed in order to block all of the mechanisms contributing to tumor vascularization. KW - vascularization model KW - tumor spheroids KW - vascular wall stem and progenitor cells KW - aortic adventitia KW - vasculogenesis KW - tumor-vessel wall-interface model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242577 VL - 10 IS - 7 ER - TY - JOUR A1 - Serfling, S. A1 - Zhi, Y. A1 - Schirbel, A. A1 - Lindner, T. A1 - Meyer, T. A1 - Gerhard-Hartmann, E. A1 - Lappa, C. A1 - Hagen, R. A1 - Hackenberg, S. A1 - Buck, A. K. A1 - Scherzad, A. T1 - Improved cancer detection in Waldeyer’s tonsillar ring by \(^{68}\)Ga-FAPI PET/CT imaging JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Purpose In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [\(^{18}\)F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [\(^{18}\)F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer’s tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer’s tonsillar ring, the novel PET tracer [\(^{68}\)Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging. Methods Eight patients with suspicion of a malignant tumor in Waldeyer’s tonsillar ring or a CUP syndrome were examined. PET/CT scans with [\(^{18}\)F]-FDG and [\(^{68}\)Ga]Ga-FAPI-4 were performed for pre-operative tumor localization. After surgical resection, histopathological and immunohistochemical results were compared to PET/CT findings. Results Histopathology revealed a palatine or lingual tonsil carcinoma in all patients. In case of lymph node metastases smaller than 7 mm in size, the [\(^{18}\)F]FDG PET/CT detection rate of cervical lymph node metastases was higher than that of [\(^{68}\)Ga]FAPI PET/CT, while both tracers identified the primary tumors in all eight cases. The size of the primary and the lymph node metastases was directly correlated to the respective FAP expression, as detected by immunohistochemistry. The mean SUVmax for the primary tumors was 21.29 ± 7.97 for \(^{18}\)F-FDG and 16.06 ± 6.29 for \(^{68}\)Ga-FAPI, respectively (p = 0.2). The mean SUVmax for the healthy contralateral tonsils was 8.38 ± 2.45 for [\(^{18}\)F]FDG and 3.55 ± 0.47 for [\(^{68}\)Ga]FAPI (p < 0.001). The SUVmax ratio of [68Ga]FAPI was significantly different from [\(^{18}\)F] FDG (p = 0.03). Mean TBRmax for the [\(^{68}\)Ga]Ga-FAPI-4 tracer was markedly higher in comparison to [\(^{18}\)F]FDG (10.90 vs. 4.11). Conclusion Non-invasive imaging of FAP expression by [\(^{68}\)Ga]FAPI PET/CT resulted in a better visual detection of the malignant primary in CUP, as compared to [\(^{18}\)F]FDG imaging. However, the detection rate of lymph node metastases was inferior, presumably due to low FAP expression in small metastases. Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [\(^{68}\)Ga]FAPI PET/CT imaging. KW - Waldeyer’s tonsillar ring KW - cancer of unknown primary (CUP) KW - positron emission tomography/computed tomography Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235271 SN - 1619-7070 VL - 48 ER - TY - JOUR A1 - Bäuerlein, Carina A. A1 - Qureischi, Musga A1 - Mokhtari, Zeinab A1 - Tabares, Paula A1 - Brede, Christian A1 - Jordán Garrote, Ana-Laura A1 - Riedel, Simone S. A1 - Chopra, Martin A1 - Reu, Simone A1 - Mottok, Anja A1 - Arellano-Viera, Estibaliz A1 - Graf, Carolin A1 - Kurzwart, Miriam A1 - Schmiedgen, Katharina A1 - Einsele, Hermann A1 - Wölfl, Matthias A1 - Schlegel, Paul-Gerhardt A1 - Beilhack, Andreas T1 - A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease JF - Frontiers in Immunology N2 - Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT. KW - acute graft-versus-host disease KW - alloreactive T cells KW - transplantation KW - prediction KW - mouse models Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224290 SN - 1664-3224 VL - 11 ER -