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1.
Clin Chest Med ; 41(2): 223-235, 2020 06.
Article in English | MEDLINE | ID: mdl-32402358

ABSTRACT

The treatment of metastatic non-small cell lung cancer (NSCLC) is constantly evolving. Although the advent of immunotherapy has played an important role in the treatment of patients with NSCLC, the identification of driver mutations and the subsequent specific treatment of these targets often lead to durable responses while maintaining quality of life. This review delves into targeted therapies available for epidermal growth factor receptor, anaplastic lymphoma kinase, ROS1, neurotrophic tropomyosin receptor kinase, and BRAF- mutated NSCLC patients, as well as other mutations with promising novel drugs under clinical investigation.


Subject(s)
Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/pathology , Neoplasm Metastasis
2.
Mucosal Immunol ; 11(5): 1398-1407, 2018 09.
Article in English | MEDLINE | ID: mdl-29907868

ABSTRACT

Immune-mediated lung is considered the result of an exacerbated innate injury immune response, although a role for adaptive lymphocytes is emerging. αß T cells specific for S. aureus enterotoxin A orchestrate a Tγδ17 response during lung injury. However, the mechanism driving IL-17 production is unclear. Here, we show a role for IL-2 triggering IL-17 production by lung granular γδ T cells as IL-17 synthesis and neutrophil recruitment was reduced by IL-2 blocking mAbs in vitro and in vivo. Mass cytometry analysis revealed that lung γδ T cells responded directly to IL-2 as evident from STAT5 phosphorylation and RoRγt expression. IL-2 receptor blocking mAbs and JAK inhibition impaired STAT5 phosphorylation and IL-17 release. Moreover, inhalation of S. aureus enterotoxin A induced IL-2 secretion and caspase-1-dependent IL-1ß activation to drive IL-17 production. This T-cell-mediated inflammasome-dependent IL-17 response is maximum when lung Tγδ17 cells were sequentially stimulated first with IL-2 then IL-1ß. Interestingly, when IL-2 is given therapeutically to cancer patients it carries a known risk of lung injury that is largely indistinguishable from that seen in sepsis. Hence, this novel mechanism reveals therapeutic targets treating both acute lung injury and high-dose IL-2 toxicity in cancer.


Subject(s)
Interleukin-17/immunology , Interleukin-1beta/immunology , Interleukin-2/immunology , Lung/immunology , T-Lymphocytes/immunology , Animals , Antibodies, Monoclonal/immunology , Caspase 1/immunology , Janus Kinases/immunology , Lung/microbiology , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , Phosphorylation/immunology , STAT5 Transcription Factor/immunology , Saccharomyces cerevisiae/immunology
3.
Am J Physiol Lung Cell Mol Physiol ; 313(1): L177-L191, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28473322

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a serious, often fatal condition without available pharmacotherapy. Although the role of innate cells in ARDS has been studied extensively, emerging evidence suggests that T cells may be involved in disease etiology. Staphylococcus aureus enterotoxins are potent T-cell mitogens capable of triggering life-threatening shock. We demonstrate that 2 days after inhalation of S. aureus enterotoxin A, mice developed T cell-mediated increases in vascular permeability, as well as expression of injury markers and caspases in the lung. Pulmonary endothelial cells underwent sequential phenotypic changes marked by rapid activation coinciding with inflammatory events secondary to T-cell priming, followed by reductions in endothelial cell number juxtaposing simultaneous T-cell expansion and cytotoxic differentiation. Although initial T-cell activation influenced the extent of lung injury, CD54 (ICAM-1) blocking antibody administered well after enterotoxin exposure substantially attenuated pulmonary barrier damage. Thus CD54-targeted therapy may be a promising candidate for further exploration into its potential utility in treating ARDS patients.


Subject(s)
Acute Lung Injury/immunology , Acute Lung Injury/pathology , Intercellular Adhesion Molecule-1/metabolism , Lung/pathology , T-Lymphocytes/immunology , Acute Lung Injury/complications , Acute Lung Injury/metabolism , Administration, Inhalation , Animals , Apoptosis/drug effects , Biomarkers/metabolism , Bronchoalveolar Lavage Fluid , Cell Count , Chemokines/metabolism , Endothelial Cells/drug effects , Endothelial Cells/pathology , Enterotoxins/administration & dosage , Enterotoxins/toxicity , Female , Inflammation/complications , Inflammation/pathology , Lymphocyte Activation/drug effects , Male , Mice, Inbred C57BL , Permeability , T-Lymphocytes/drug effects
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