Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/23319
Title: Harnessing natural killer immunity in metastatic small cell lung cancer.
Authors: Best, Sarah A;Hess, Jonas;Souza-Fonseca-Guimaraes, Fernando;Cursons, Joseph;Kersbergen, Ariena;Dong, Xueyi;Rautela, Jai;Hyslop, Stephanie R;Ritchie, Matthew E;Davis, Melissa J;Leong, Tracy L;Irving, Louis;Steinfort, Daniel;Huntington, Nicholas D;Sutherland, Kate D
Affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
Translational Research Institute, Brisbane, Queensland, Australia
University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
School of Mathematics and Statistics, The University of Melbourne, Parkville, Australia
Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Respiratory Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 26-May-2020
EDate: 2020-05-26
Citation: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2020; online first: 26 May
Abstract: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer and though most patients initially respond to platinum-based chemotherapy, resistance rapidly develops. Immunotherapy has promise in the treatment of lung cancer, however SCLC patients exhibit poor overall responses highlighting the necessity for alternative approaches. Natural killer (NK) cells are an alternative to T cell-based immunotherapies, that do not require sensitization to antigens presented on the surface of tumor cells. We investigated the immunophenotype of human SCLC tumors by both flow cytometry on fresh samples and bioinformatic analysis. Cell lines generated from murine SCLC were transplanted into mice lacking key cytotoxic immune cells. Subcutaneous tumor growth, metastatic dissemination and the activation of CD8+ T and NK cells were evaluated by histology and flow cytometry. Transcriptomic analysis of human SCLC tumors revealed heterogeneous immune checkpoint and cytotoxic signature profiles. Utilizing sophisticated genetically engineered mouse models, we demonstrated that the absence of NK cells, but not CD8+ T cells, significantly enhanced metastatic dissemination of SCLC tumor cells in vivo. Moreover, hyperactivation of NK cell activity through augmentation of IL-15 or TGF-β signaling pathways ameliorated SCLC metastases, an effect which was enhanced when combined with anti-PD1 therapy. These proof-of-principle findings provide a rationale for exploiting the anti-tumor functions of NK cells in the treatment of SCLC patients. Moreover, the distinct immune profiles of SCLC subtypes reveal an unappreciated level of heterogeneity that warrants further investigation in the stratification of patients for immunotherapy.
URI: http://ahro.austin.org.au/austinjspui/handle/1/23319
DOI: 10.1016/j.jtho.2020.05.008
PubMed URL: 32470639
Type: Journal Article
Subjects: Natural Killer (NK) cells
Programmed cell death 1 (PD1)
Small cell lung cancer (SCLC)
genetically engineered mouse models (GEMMs)
metastasis
Appears in Collections:Journal articles

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