Harnessing Natural Killer Immunity in Metastatic SCLC
| Autor: | Jonas B. Hess, Louis Irving, Tracy L. Leong, Jai Rautela, Stephanie R. Hyslop, Ariena Kersbergen, Nicholas D. Huntington, Matthew E. Ritchie, Joseph Cursons, Sarah A. Best, Melissa J. Davis, Daniel P Steinfort, Xueyi Dong, Kate D. Sutherland, Fernando Souza-Fonseca-Guimaraes |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Lung Neoplasms T cell medicine.medical_treatment T-Lymphocytes 03 medical and health sciences Mice 0302 clinical medicine Immunophenotyping Immune system Antigen medicine Cytotoxic T cell Animals Humans business.industry Immunotherapy Immune checkpoint respiratory tract diseases Killer Cells Natural 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research business CD8 |
| Zdroj: | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 15(9) |
| ISSN: | 1556-1380 |
| Popis: | Introduction SCLC is the most aggressive subtype of lung cancer, and though most patients initially respond to platinum-based chemotherapy, resistance develops rapidly. Immunotherapy holds promise in the treatment of lung cancer; however, patients with SCLC 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. Methods 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 activation of CD8+ T and NK cells were evaluated by histology and flow cytometry. Results Transcriptomic analysis of human SCLC tumors revealed heterogeneous immune checkpoint and cytotoxic signature profiles. Using sophisticated, genetically engineered mouse models, we reported that the absence of NK cells, but not CD8+ T cells, substantially enhanced metastatic dissemination of SCLC tumor cells in vivo. Moreover, hyperactivation of NK cell activity through augmentation of interleukin-15 or transforming growth factor-β signaling pathways ameliorated SCLC metastases, an effect that was enhanced when combined with antiprogrammed cell death-1 therapy. Conclusions These proof-of-principle findings provide a rationale for exploiting the antitumor functions of NK cells in the treatment of patients with SCLC. 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. |
| Databáze: | OpenAIRE |
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