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M1 macrophage recruitment correlates with worse outcome in SHH Medulloblastomas

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BACKGROUND: Recent progress in molecular analysis has advanced the understanding of medulloblastoma (MB) and is anticipated to facilitate management of the disease. MB is composed of 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Macrophages play a crucial role in the tumor microenvironment; however, the functional role of their activated phenotype (M1/M2) remains controversial. Herein, we investigate the correlation between tumor-associated macrophage (TAM) recruitment within the MB subgroups and prognosis. METHODS: Molecular subgrouping was performed by a nanoString-based RNA assay on retrieved snap-frozen tissue samples. Immunohistochemistry (IHC) and immunofluorescence (IF) assays were performed on subgroup identified samples, and the number of polarized macrophages was quantified from IHC. Survival analyses were conducted on collected clinical data and quantified macrophage data. RESULTS: TAM (M1/M2) recruitment in SHH MB was significantly higher compared to that in other subgroups. A Kaplan-Meier survival curve and multivariate Cox regression demonstrated that high M1 expressers showed worse overall survival (OS) and progression-free survival (PFS) than low M1 expressers in SHH MB, with relative risk (RR) values of 11.918 and 6.022, respectively. CONCLUSION: M1 rather than M2 correlates more strongly with worse outcome in SHH medulloblastoma.

Author Info: (1) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (2) Medical Research Collaborating Center, Seoul National

Author Info: (1) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (2) Medical Research Collaborating Center, Seoul National University Hospital, Seoul, South Korea. (3) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (4) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (5) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. (6) Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea. (7) Department of Pathology, Yonsei University, College of Medicine, Severance Hospital, Seoul, Republic of Korea. (8) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea. (9) Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, 101 Daehakro, Jongno-gu, 110-744, Seoul, Republic of Korea. phi.jihoon@gmail.com.

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Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil

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BACKGROUND: Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. METHODS: Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 - ML (linear tetra-epitope) and T7 - MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while CD3(+)/CD8(+), CD3(+)/CD4(+) T cells and MDSCs were evaluated by flow cytometry. RESULTS: In vitro, rapid TNF-alpha and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 - MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 - MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, CD3(+)/CD8(+) and CD3(+)/CD4(+) T cells. 5-FU also enhanced the T7 - MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 - MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 - MB alone or in combination with 5-FU on the prophylactic schedule. CONCLUSIONS: A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 - MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition.

Author Info: (1) School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. (2) The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, 518001, Guangdong

Author Info: (1) School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. (2) The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, 518001, Guangdong, China. (3) Department of Biology and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China. (4) School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. (5) The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, 518001, Guangdong, China. (6) School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. (7) School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. (8) School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. (9) School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. gyjin@szu.edu.cn. Cancer Research Center, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, China. gyjin@szu.edu.cn.

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A genome-wide survey of mutations in the Jurkat cell line

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BACKGROUND: The Jurkat cell line has an extensive history as a model of T cell signaling. But at the turn of the 21st century, some expression irregularities were observed, raising doubts about how closely the cell line paralleled normal human T cells. While numerous expression deficiencies have been described in Jurkat, genetic explanations have only been provided for a handful of defects. RESULTS: Here, we report a comprehensive catolog of genomic variation in the Jurkat cell line based on whole-genome sequencing. With this list of all detectable, non-reference sequences, we prioritize potentially damaging mutations by mining public databases for functional effects. We confirm documented mutations in Jurkat and propose links from detrimental gene variants to observed expression abnormalities in the cell line. CONCLUSIONS: The Jurkat cell line harbors many mutations that are associated with cancer and contribute to Jurkat's unique characteristics. Genes with damaging mutations in the Jurkat cell line are involved in T-cell receptor signaling (PTEN, INPP5D, CTLA4, and SYK), maintenance of genome stability (TP53, BAX, and MSH2), and O-linked glycosylation (C1GALT1C1). This work ties together decades of molecular experiments and serves as a resource that will streamline both the interpretation of past research and the design of future Jurkat studies.

Author Info: (1) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, 92037, USA. lhgioia@scripps.edu. (2) Next Generation Sequencing Core, The Scripps Research Institute, La

Author Info: (1) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, 92037, USA. lhgioia@scripps.edu. (2) Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, 92037, USA. (3) Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, 92037, USA. (4) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, 92037, USA. (5) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, 92037, USA.

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Cytomegalovirus: an unlikely ally in the fight against blood cancers

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CMV infection is a potentially fatal complication in patients receiving HSCT, but recent evidence indicates that CMV has strong anti-leukemia effects due in part to shifts in the composition of NK-cell subsets. NK-cells are the primary mediators of the anti-leukemia effect of allogeneic HSCT and infusion of allogeneic NK-cells has shown promise as a means of inducing remission and preventing relapse of several different hematologic malignancies. The effectiveness of these treatments is limited, however, when tumors express HLA-E, a ligand for the inhibitory receptor NKG2A which is expressed by the vast majority of post-transplant reconstituted and ex vivo expanded NK-cells. It is possible to enhance NK-cell cytotoxicity against HLA-E(pos) malignancies by increasing the proportion of NK-cells expressing NKG2C (the activating receptor for HLA-E) and lacking the corresponding inhibitory receptor NKG2A. The proportion of NKG2C(pos) /NKG2A(neg) NK-cells is typically low in healthy adults, but it can be increased by CMV infection or ex vivo expansion of NK-cells using HLA-E transfected feeder cells and IL-15. In this review, we will discuss the role of CMV-driven NKG2C(pos) /NKG2A(neg) NK-cell expansion on anti-tumor cytotoxicity and disease progression in the context of hematologic malignancies, and explore the possibility of harnessing NKG2C(pos) /NKG2A(neg) NK-cells for cancer immunotherapy. This article is protected by copyright. All rights reserved.

Author Info: (1) Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, 3875 Holman Street, Houston, Texas, 77204, USA. Department of Nutritional Sciences

Author Info: (1) Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, 3875 Holman Street, Houston, Texas, 77204, USA. Department of Nutritional Sciences, The University of Arizona, 1177 E. Fourth Street, Tucson, Arizona, 85721, USA. (2) Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, 3875 Holman Street, Houston, Texas, 77204, USA. Department of Nutritional Sciences, The University of Arizona, 1177 E. Fourth Street, Tucson, Arizona, 85721, USA. (3) Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, 3875 Holman Street, Houston, Texas, 77204, USA. Department of Nutritional Sciences, The University of Arizona, 1177 E. Fourth Street, Tucson, Arizona, 85721, USA.

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hIL-15-gene modified human natural killer cells (NKL-IL15) exhibit anti-human leukemia functions

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PURPOSE: Natural killer (NK) cells can kill transformed cells and represent anti-tumor activities for improving the immunotherapy of cancer. In previous works, we established human interleukin-15 (hIL-15) gene-modified NKL cells (NKL-IL15) and demonstrated their efficiency against human hepatocarcinoma cells (HCCs) in vitro and in vivo. To further assess the applicability of NKL-IL15 cells in adoptive cellular immunotherapy for human leukemia, here we report their natural cytotoxicity against leukemia in vitro and in vivo. METHODS: Flow cytometry, ELISA and MTT methods were performed for molecular expression, cell proliferation and cytotoxicity assays. Leukemia xenograft NOD/SCID mice were established by subcutaneous injection with K562 cells, and then treated with irradiated NKL cells. RESULTS: We found NKL-IL15 cells displayed a significant high cytolysis activity against both human leukemia cell lines and primary leukemia cells from patients, accompanied with up-regulated expression of molecules related to NK cell cytotoxicity such as perforin, granzyme B and NKp80. Moreover, cytokines secreted by NKL-IL15 cells, including TNF-alpha and IFN-gamma, could induce the expression of NKG2D ligands on target cells, which increased the susceptibility of leukemia cells to NK cell-mediated cytolysis. Encouragingly, NKL-IL15 cells significantly inhibited the growth of leukemia cells in xenografted NOD/SCID mice and prolonged the survival of tumor-bearing mice dramatically. Furthermore, NKL-IL15 cells displayed stimulatory effects on hPBMCs, indicating the immunesuppressive status of leukemia patients could be improved by NKL-IL15 cell treatment. CONCLUSIONS: These results provided evidence that IL-15 gene-modification could augment NK cell-mediated anti-human leukemia function, which would improve primary NK cell-based immunotherapy for leukemia in future.

Author Info: (1) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (2) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical

Author Info: (1) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (2) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (3) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. (4) Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. zhangj65@sdu.edu.cn.

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VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival

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Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

Author Info: (1) Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Department of Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA. (2) Department of Pathology

Author Info: (1) Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Department of Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA. (2) Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (3) Biostatistics Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchock Medical Center, Lebanon, NH, USA. (4) Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (5) Departments of Biomedical Data Sciences, Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, USA. (6) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. (7) Department of Surgery, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. (8) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. (9) Roswell Park Cancer Institute, University of Buffalo, The State University of New York, Elm and Carlton, Buffalo, NY, 14263, USA. marc.ernstoff@roswellpark.org.

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Induction of necrotic cell death and activation of STING in the tumor microenvironment via cationic silica nanoparticles leading to enhanced antitumor immunity

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Nanotechnology has demonstrated tremendous clinical utility, with potential applications in cancer immunotherapy. Although nanoparticles with intrinsic cytotoxicity are often considered unsuitable for clinical applications, such toxicity may be harnessed in the fight against cancer. Nanoparticle-associated toxicity can induce acute necrotic cell death, releasing tumor-associated antigens which may be captured by antigen-presenting cells to initiate or amplify tumor immunity. To test this hypothesis, cytotoxic cationic silica nanoparticles (CSiNPs) were directly administered into B16F10 melanoma implanted in C57BL/6 mice. CSiNPs caused plasma membrane rupture and oxidative stress of tumor cells, inducing local inflammation, tumor cell death and the release of tumor-associated antigens. The CSiNPs were further complexed with bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), a molecular adjuvant which activates the stimulator of interferon genes (STING) in antigen-presenting cells. Compared with unformulated c-di-GMP, the delivery of c-di-GMP with CSiNPs markedly prolonged its local retention within the tumor microenvironment and activated tumor-infiltrating antigen-presenting cells. The combination of CSiNPs and a STING agonist showed dramatically increased expansion of antigen-specific CD8+ T cells, and potent tumor growth inhibition in murine melanoma. These results demonstrate that cationic nanoparticles can be used as an effective in situ vaccine platform which simultaneously causes tumor destruction and immune activation.

Author Info: (1) Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan 48202, USA. haipengl.liu@wayne.edu. (2) Department of Chemical Engineering and Materials Science, Wayne

Author Info: (1) Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan 48202, USA. haipengl.liu@wayne.edu. (2) Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan 48202, USA. haipengl.liu@wayne.edu. (3) Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan 48202, USA. haipengl.liu@wayne.edu. (4) Department of Oncology, Wayne State University, Detroit, Michigan 48201, USA and Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, USA. (5) Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan 48202, USA. haipengl.liu@wayne.edu. (6) Department of Oncology, Wayne State University, Detroit, Michigan 48201, USA and Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, USA. (7) Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan 48202, USA. haipengl.liu@wayne.edu and Department of Oncology, Wayne State University, Detroit, Michigan 48201, USA and Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, USA.

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IL-35-producing B cells in gastric cancer patients

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A significant characteristic of advanced gastric cancer (GC) is immune suppression, which can promote the progression of GC. Interleukin 35 (IL-35) is an immune-suppressing cytokine, and it is generally recognized that this cytokine is secreted by regulatory T (Treg) cells. Recently, studies have found that IL-35 can also be produced by B cells in mice. However, scientific studies reporting that IL-35 is secreted by B cells in humans, specifically in cancer patients, are very rare.Blood samples were collected from 30 healthy controls (HCs) and 50 untreated GC patients, and IL-35-producing B cells in the peripheral blood were investigated. Moreover, Treg cells (CD4CD25CD127), myeloid-derived suppressor cells (MDSCs) (CD14HLA-DR) and other lymphocyte subsets (CD3, CD4, CD8 T cells, activated and memory CD4 T cells, activated CD8 T cells, CD14 monocytes, and IL-10-producing B cells) were also examined.IL-35-producing B cells were significantly upregulated in patients with advanced GC. Furthermore, the frequency of IL-35-producing B cells was positively correlated with the frequencies of Treg cells (CD4CD25CD127), MDSCs (CD14HLA-DR), IL-10-producing B cells, and CD14 monocytes in these GC patients.In summary, the frequency of IL-35-producing B cells is significantly elevated in advanced GC; this outcome implies that this group of B cells may participate in GC progression.

Author Info: (1) Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou. (2) Department of Pharmacology, JiangXi Medical College, Shangrao, China. (3) Department of Gastroenterology

Author Info: (1) Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou. (2) Department of Pharmacology, JiangXi Medical College, Shangrao, China. (3) Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou.

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Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

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BACKGROUND: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. METHOD: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. RESULTS: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. CONCLUSION: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.

Author Info: (1) (2)

Author Info: (1) (2)

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Single-Molecule Light-Sheet Imaging of Suspended T Cells

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Adaptive immune responses are initiated by triggering of the T cell receptor. Single-molecule imaging based on total internal reflection fluorescence microscopy at coverslip/basal cell interfaces is commonly used to study this process. These experiments have suggested, unexpectedly, that the diffusional behavior and organization of signaling proteins and receptors may be constrained before activation. However, it is unclear to what extent the molecular behavior and cell state is affected by the imaging conditions, i.e., by the presence of a supporting surface. In this study, we implemented single-molecule light-sheet microscopy, which enables single receptors to be directly visualized at any plane in a cell to study protein dynamics and organization in live, resting T cells. The light sheet enabled the acquisition of high-quality single-molecule fluorescence images that were comparable to those of total internal reflection fluorescence microscopy. By comparing the apical and basal surfaces of surface-contacting T cells using single-molecule light-sheet microscopy, we found that most coated-glass surfaces and supported lipid bilayers profoundly affected the diffusion of membrane proteins (T cell receptor and CD45) and that all the surfaces induced calcium influx to various degrees. Our results suggest that, when studying resting T cells, surfaces are best avoided, which we achieve here by suspending cells in agarose.

Author Info: (1) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. (2) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. (3) Department of Chemistry, University

Author Info: (1) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. (2) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. (3) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. (4) Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. (5) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. (6) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. (7) Radcliffe Department of Medicine and MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. Electronic address: simon.davis@imm.ox.ac.uk. (8) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. Electronic address: dk10012@cam.ac.uk. (9) Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. Electronic address: sl591@cam.ac.uk.

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