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  1. Article ; Online: Multiplex Immunohistochemistry Analysis of Melanoma Tumor-Infiltrating Lymphocytes.

    Nguyen, Thu / Kocovski, Nikolce / Macdonald, Sean / Yeang, Han Xian Aw / Wang, Minyu / Neeson, Paul J

    Methods in molecular biology (Clifton, N.J.)

    2021  Volume 2265, Page(s) 557–572

    Abstract: Tumor-infiltrating lymphocytes (TILs) are an important prognostic indicator in melanoma and play a key role in the patient's response to immune checkpoint blockade. However, until recently, it was not possible to combine multi-parameter markers to define ...

    Abstract Tumor-infiltrating lymphocytes (TILs) are an important prognostic indicator in melanoma and play a key role in the patient's response to immune checkpoint blockade. However, until recently, it was not possible to combine multi-parameter markers to define the TILs and their histological context. Multiplex immunohistochemistry (mIHC) is a new technology which addresses this issue and enables simultaneous detection of melanoma and multiple immune subsets in formalin fixed paraffin embedded tissue. Following antigen retrieval, melanoma tissue sections are stained by OPAL on an autostainer, including serial rounds of epitope labelling with monoclonal antibodies followed by tyramide signal amplification (TSA). The stained tissue sections are then imaged on the Vectra instrument, and digital images are processed by analysis software (inForm and HALO) to derive tissue segmentation and immune subset densities within the tumor and tumor stroma. Spatial relationships between immune cells and tumor cells are then analyzed using a novel R algorithm. Taken together, multiplex IHC describes the histological context of the immune system in melanoma. The data is objective and allows for characterization of individual melanomas as T cell inflamed (hot), immune excluded, or no immune cells (cold).
    MeSH term(s) Biomarkers, Tumor/metabolism ; Humans ; Immunohistochemistry ; Lymphocytes, Tumor-Infiltrating/metabolism ; Lymphocytes, Tumor-Infiltrating/pathology ; Melanoma/metabolism ; Melanoma/pathology ; Tumor Microenvironment
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2021-03-11
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1205-7_39
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Using Mass Cytometry to Analyze the Tumor-Infiltrating Lymphocytes in Human Melanoma.

    Tantalo, Daniela / Nguyen, Thu / Yeang, Han Xian Aw / Zhu, Joe / Macdonald, Sean / Wang, Minyu / de Silva, Harini / D'Souza, Criselle / Pizzolla, Angela / Neeson, Paul J

    Methods in molecular biology (Clifton, N.J.)

    2021  Volume 2265, Page(s) 543–555

    Abstract: Here we describe the application of mass cytometry to analyze tumor-infiltrating lymphocytes in human melanoma. Mass cytometry is the coupling of flow cytometry and mass spectrometry, which allows for the simultaneous measurement of 40+ cell parameters ... ...

    Abstract Here we describe the application of mass cytometry to analyze tumor-infiltrating lymphocytes in human melanoma. Mass cytometry is the coupling of flow cytometry and mass spectrometry, which allows for the simultaneous measurement of 40+ cell parameters on a per cell basis. Heavy metal-labeled antibodies can bind to proteins (CD markers, transcription factors, cytokines) on the cell surface and in the cytoplasm/nucleus. As labeled cells pass through the CyTOF, the instrument detects the heavy metals. Combining these signals allows description of melanoma tumor-infiltrating lymphocytes at a greater depth than alternative phenotyping strategies and enables detailed analyses of a variety of cellular parameters, including immune cell lineage, activation status, and functional polarization.
    MeSH term(s) Flow Cytometry ; Humans ; Lymphocytes, Tumor-Infiltrating/metabolism ; Lymphocytes, Tumor-Infiltrating/pathology ; Mass Spectrometry ; Melanoma/metabolism ; Melanoma/pathology ; Single-Cell Analysis
    Language English
    Publishing date 2021-03-11
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1205-7_38
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The efficacy of combination treatment with elotuzumab and lenalidomide is dependent on crosstalk between natural killer cells, monocytes and myeloma cells.

    Richardson, Kelden / Keam, Simon P / Zhu, Joe Jiang / Meyran, Deborah / D'Souza, Criselle / Macdonald, Sean / Campbell, Kerry / Robbins, Michael / Bezman, Natalie A / Todd, Kirsten / Quach, Hang / Ritchie, David S / Harrison, Simon J / Prince, H Miles / Trapani, Joseph A / Jenkins, Misty R / Beavis, Paul A / Darcy, Phillip K / Neeson, Paul J

    Haematologica

    2023  Volume 108, Issue 1, Page(s) 83–97

    Abstract: Patients with refractory relapsed multiple myeloma respond to combination treatment with elotuzumab and lenalidomide. The mechanisms underlying this observation are not fully understood. Furthermore, biomarkers predictive of response have not been ... ...

    Abstract Patients with refractory relapsed multiple myeloma respond to combination treatment with elotuzumab and lenalidomide. The mechanisms underlying this observation are not fully understood. Furthermore, biomarkers predictive of response have not been identified to date. To address these issues, we used a humanized myeloma mouse model and adoptive transfer of human natural killer (NK) cells to show that elotuzumab and lenalidomide treatment controlled myeloma growth, and this was mediated through CD16 on NK cells. In co-culture studies, we showed that peripheral blood mononuclear cells from a subset of patients with refractory relapsed multiple myeloma were effective killers of OPM2 myeloma cells when treated with elotuzumab and lenalidomide, and this was associated with significantly increased expression of CD54 on OPM2 cells. Furthermore, elotuzumab- and lenalidomide-induced OPM2 cell killing and increased OPM2 CD54 expression were dependent on both monocytes and NK cells, and these effects were not mediated by soluble factors alone. At the transcript level, elotuzumab and lenalidomide treatment significantly increased OPM2 myeloma cell expression of genes for trafficking and adhesion molecules, NK cell activation ligands and antigen presentation molecules. In conclusion, our findings suggest that multiple myeloma patients require elotuzumab- and lenalidomide-mediated upregulation of CD54 on autologous myeloma cells, in combination with NK cells and monocytes to mediate an effective anti-tumor response. Furthermore, our data suggest that increased myeloma cell CD54 expression levels could be a powerful predictive biomarker for response to elotuzumab and lenalidomide treatment.
    MeSH term(s) Animals ; Mice ; Humans ; Lenalidomide/pharmacology ; Lenalidomide/therapeutic use ; Lenalidomide/metabolism ; Multiple Myeloma/metabolism ; Monocytes/metabolism ; Leukocytes, Mononuclear/metabolism ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Killer Cells, Natural ; Dexamethasone/therapeutic use
    Chemical Substances Lenalidomide (F0P408N6V4) ; elotuzumab (1351PE5UGS) ; Dexamethasone (7S5I7G3JQL)
    Language English
    Publishing date 2023-01-01
    Publishing country Italy
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2021.279930
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Single-Fraction vs Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases (SAFRON II): The Trans Tasman Radiation Oncology Group 13.01 Phase 2 Randomized Clinical Trial.

    Siva, Shankar / Bressel, Mathias / Mai, Tao / Le, Hien / Vinod, Shalini / de Silva, Harini / Macdonald, Sean / Skala, Marketa / Hardcastle, Nicholas / Rezo, Angela / Pryor, David / Gill, Suki / Higgs, Braden / Wagenfuehr, Kassandra / Montgomery, Rebecca / Awad, Raef / Chesson, Brent / Eade, Thomas / Wong, Wenchang /
    Sasso, Giuseppe / De Abreu Lourenco, Richard / Kron, Tomas / Ball, David / Neeson, Paul

    JAMA oncology

    2021  Volume 7, Issue 10, Page(s) 1476–1485

    Abstract: Importance: Evidence is lacking from randomized clinical trials to guide the optimal approach for stereotactic ablative body radiotherapy (SABR) in patients with pulmonary oligometastases.: Objective: To assess whether single-fraction or ... ...

    Abstract Importance: Evidence is lacking from randomized clinical trials to guide the optimal approach for stereotactic ablative body radiotherapy (SABR) in patients with pulmonary oligometastases.
    Objective: To assess whether single-fraction or multifraction SABR is more effective for the treatment of patients with pulmonary oligometastases.
    Design, setting, and participants: This multicenter, unblinded, phase 2 randomized clinical trial of 90 patients across 13 centers in Australia and New Zealand enrolled patients with 1 to 3 lung oligometastases less than or equal to 5 cm from any nonhematologic malignant tumors located away from the central airways, Eastern Cooperative Oncology Group performance status 0 or 1, and all primary and extrathoracic disease controlled with local therapy. Enrollment was from January 1, 2015, to December 31, 2018, with a minimum patient follow-up of 2 years.
    Interventions: Single fraction of 28 Gy (single-fraction arm) or 4 fractions of 12 Gy (multifraction arm) to each oligometastasis.
    Main outcomes and measures: The main outcome was grade 3 or higher treatment-related adverse events (AEs) occurring within 1 year of SABR. Secondary outcomes were freedom from local failure, overall survival, disease-free survival, and patient-reported outcomes (MD Anderson Symptom Inventory-Lung Cancer and EuroQol 5-dimension visual analog scale).
    Results: Ninety participants were randomized, of whom 87 were treated for 133 pulmonary oligometastases. The mean (SD) age was 66.6 [11.6] years; 58 (64%) were male. Median follow-up was 36.5 months (interquartile range, 24.8-43.9 months). The numbers of grade 3 or higher AEs related to treatment at 1 year were 2 (5%; 80% CI, 1%-13%) in the single-fraction arm and 1 (3%; 80% CI, 0%-10%) in the multifraction arm, with no significant difference observed between arms. One grade 5 AE occurred in the multifraction arm. No significant differences were found between the multifraction arm and single-fraction arm for freedom from local failure (hazard ratio [HR], 0.5; 95% CI, 0.2-1.3; P = .13), overall survival (HR, 1.5; 95% CI, 0.6-3.7; P = .44), or disease-free survival (HR, 1.0; 95% CI, 0.6-1.6; P > .99). There were no significant differences observed in patient-reported outcomes.
    Conclusions and relevance: In this randomized clinical trial, neither arm demonstrated evidence of superior safety, efficacy, or symptom burden; however, single-fraction SABR is more efficient to deliver. Therefore, single-fraction SABR, as assessed by the most acceptable outcome profile from all end points, could be chosen to escalate to future studies.
    Trial registration: ClinicalTrials.gov Identifier: NCT01965223.
    MeSH term(s) Child ; Humans ; Lung ; Male ; Neoplasms/etiology ; Progression-Free Survival ; Proportional Hazards Models ; Radiosurgery/adverse effects ; Radiosurgery/methods ; Treatment Outcome
    Language English
    Publishing date 2021-08-28
    Publishing country United States
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ISSN 2374-2445
    ISSN (online) 2374-2445
    DOI 10.1001/jamaoncol.2021.2939
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  5. Article ; Online: Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma.

    Jacquelot, Nicolas / Seillet, Cyril / Wang, Minyu / Pizzolla, Angela / Liao, Yang / Hediyeh-Zadeh, Soroor / Grisaru-Tal, Sharon / Louis, Cynthia / Huang, Qiutong / Schreuder, Jaring / Souza-Fonseca-Guimaraes, Fernando / de Graaf, Carolyn A / Thia, Kevin / Macdonald, Sean / Camilleri, Mary / Luong, Kylie / Zhang, Shengbo / Chopin, Michael / Molden-Hauer, Tristan /
    Nutt, Stephen L / Umansky, Viktor / Ciric, Bogoljub / Groom, Joanna R / Foster, Paul S / Hansbro, Philip M / McKenzie, Andrew N J / Gray, Daniel H D / Behren, Andreas / Cebon, Jonathan / Vivier, Eric / Wicks, Ian P / Trapani, Joseph A / Munitz, Ariel / Davis, Melissa J / Shi, Wei / Neeson, Paul J / Belz, Gabrielle T

    Nature immunology

    2021  Volume 22, Issue 7, Page(s) 851–864

    Abstract: Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically ... ...

    Abstract Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
    MeSH term(s) Animals ; Antibodies/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Cell Line, Tumor ; Chemotaxis, Leukocyte/drug effects ; Cytotoxicity, Immunologic/drug effects ; Eosinophils/drug effects ; Eosinophils/immunology ; Eosinophils/metabolism ; Female ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Interleukin-33/pharmacology ; Lymphocytes/drug effects ; Lymphocytes/immunology ; Lymphocytes/metabolism ; Male ; Melanoma, Experimental/drug therapy ; Melanoma, Experimental/genetics ; Melanoma, Experimental/immunology ; Melanoma, Experimental/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/metabolism ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/immunology ; Skin Neoplasms/metabolism ; Mice
    Chemical Substances Antibodies ; Immune Checkpoint Inhibitors ; Interleukin-33 ; PDCD1 protein, human ; Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
    Language English
    Publishing date 2021-06-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/s41590-021-00943-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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