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1.
Front Oncol ; 13: 1129195, 2023.
Article in English | MEDLINE | ID: mdl-37143952

ABSTRACT

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. Immunotherapy with immune checkpoint inhibitors (ICI) has significantly improved outcomes in some patients, however 80-85% of patients receiving immunotherapy develop primary resistance, manifesting as a lack of response to therapy. Of those that do have an initial response, disease progression may occur due to acquired resistance. The make-up of the tumour microenvironment (TME) and the interaction between tumour infiltrating immune cells and cancer cells can have a large impact on the response to immunotherapy. Robust assessment of the TME with accurate and reproducible methods is vital to understanding mechanisms of immunotherapy resistance. In this paper we will review the evidence of several methodologies to assess the TME, including multiplex immunohistochemistry, imaging mass cytometry, flow cytometry, mass cytometry and RNA sequencing.

2.
Cancer Cell ; 41(5): 837-852.e6, 2023 05 08.
Article in English | MEDLINE | ID: mdl-37086716

ABSTRACT

Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Memory T Cells , Immunologic Memory , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung , CD8-Positive T-Lymphocytes
3.
EMBO Mol Med ; 14(4): e14608, 2022 04 07.
Article in English | MEDLINE | ID: mdl-34927798

ABSTRACT

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.


Subject(s)
Antineoplastic Agents , Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Child , Disease Models, Animal , Genomics/methods , Humans , Neoplasms/pathology , Precision Medicine/methods , Xenograft Model Antitumor Assays
4.
Immunity ; 54(8): 1758-1771.e7, 2021 08 10.
Article in English | MEDLINE | ID: mdl-34256013

ABSTRACT

Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease.


Subject(s)
Apoptosis/immunology , Macrophages/immunology , Mycobacterium tuberculosis/immunology , Neutrophils/immunology , Tuberculosis, Pulmonary/immunology , Animals , Caspase 8/genetics , Caspase 8/metabolism , Cell Line , Dipeptides/therapeutic use , Humans , Indoles/therapeutic use , Lymphocyte Activation/immunology , Macrophages/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/microbiology , Protein Kinases/genetics , Protein Kinases/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , T-Lymphocytes/immunology , Thiazoles/therapeutic use , Tuberculosis, Pulmonary/drug therapy
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