Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression.

The expression of PD-L1 on tumor cells (TC) is used as an immunotherapy biomarker in lung cancer, but heterogeneous intratumoral expression is often observed. To better understand heterogeneity in the lung cancer tumor microenvironment, we performed proteomic and whole-transcriptomic digital spatial profiling analyses of TCs and immune cells (IC) in spatially matched areas based on tumor PD-L1 expression and the status of the immune microenvironment. We validated our findings using IHC, data from The Cancer Genome Atlas, and immunotherapy cohorts.

Transcriptomic Heterogeneity of EGFR-Mutant Non-Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer.

Purpose: Histologic transformation from EGFR-mutant non-small cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored.

Experimental Design: We conducted whole-transcriptome analysis of 59 regions of interest through the spatial profiling of formalin-fixed, paraffin-embedded tissues obtained from 10 patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; and t-SCLC, 30 regions of interests).

Epithelial-mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer.

Background: We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy.

Methods: PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice.

CRIF1 deficiency induces FOXP3 inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity.

Recently identified human FOXP3CD45RA inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (T). In spite of their implication in tumors, the mechanism for generation of FOXP3CD45RA INS cells in vivo is unclear. We showed that the FOXP3CD45RA cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator.

Innate Type-2 Cytokines: From Immune Regulation to Therapeutic Targets.

The intricate role of innate type-2 cytokines in immune responses is increasingly acknowledged for its dual nature, encompassing both protective and pathogenic dimensions. Ranging from defense against parasitic infections to contributing to inflammatory diseases like asthma, fibrosis, and obesity, these cytokines intricately engage with various innate immune cells. This review meticulously explores the cellular origins of innate type-2 cytokines and their intricate interactions, shedding light on factors that amplify the innate type-2 response, including TSLP, IL-25, and IL-33.

Comprehensive Transcriptomic Analysis for Thymic Epithelial Cells of Aged Mice and Humans.

Thymic epithelial cells (TECs) play a critical role in thymic development and thymopoiesis. As individuals age, TECs undergo various changes that impact their functions, leading to a reduction in cell numbers and impaired thymic selection. These age-related alterations have been observed in both mice and humans.

De novo fatty-acid synthesis protects invariant NKT cells from cell death, thereby promoting their homeostasis and pathogenic roles in airway hyperresponsiveness.

Invariant natural-killer T (NKT) cells play pathogenic roles in allergic asthma in murine models and possibly also humans. While many studies show that the development and functions of innate and adaptive immune cells depend on their metabolic state, the evidence for this in NKT cells is very limited. It is also not clear whether such metabolic regulation of NKT cells could participate in their pathogenic activities in asthma.

Comparison of Two Variant Analysis Programs for Next-Generation Sequencing Data of Whole Mitochondrial Genome.

Background: With advance of next-generation sequencing (NGS) techniques, the need for mitochondrial DNA analysis is increasing not only in the forensic area, but also in medical fields.

Methods: Two commercial programs, Converge Software (CS) and Torrent Variant Caller for variant calling of NGS data, were compared with a considerable amount of sequence data of 50 samples with a homogeneous ethnicity.

Results: About 2,300 variants were identified and the two programs showed about 90% of consistency.

Invariant natural killer T cells in lung diseases.

Invariant natural killer T (iNKT) cells are a subset of T cells that are characterized by a restricted T-cell receptor (TCR) repertoire and a unique ability to recognize glycolipid antigens. These cells are found in all tissues, and evidence to date suggests that they play many immunological roles in both homeostasis and inflammatory conditions. The latter include lung inflammatory diseases such as asthma and infections: the roles of lung-resident iNKT cells in these diseases have been extensively researched.

Computed Tomography-based Prognostication in Lung Adenocarcinomas through Histopathological Feature Learning: A Retrospective Multicenter Study.

Modeling imaging surrogates for well-validated histopathological risk factors would enable prognostication in early-stage lung adenocarcinomas. We aimed to develop and validate computed tomography (CT)-based deep learning (DL) models for the prognostication of early-stage lung adenocarcinomas through learning histopathological features and to investigate the models' reproducibility using retrospective, multicenter datasets. Two DL models were trained to predict visceral pleural invasion and lymphovascular invasion, respectively, using preoperative chest CT scans from 1,426 patients with stage I-IV lung adenocarcinomas.

Triple-Negative Breast Cancer-Derived Extracellular Vesicles Promote a Hepatic Premetastatic Niche via a Cascade of Microenvironment Remodeling.

Unlabelled: Patients with triple-negative breast cancer (TNBC) often develop metastases in visceral organs including the liver, but the detailed molecular mechanisms of TNBC liver metastasis is not clearly understood. In this study, we tried to dissect the process of premetastatic niche formation in the liver by using patient-derived xenograft (PDX) models of TNBC with different metastatic propensity. RNA sequencing of TNBC PDX models that successfully metastasized to liver showed upregulation of the Cx3cr1 gene in the liver microenvironment.

Whole Mitochondrial Genome Analysis in Non-Small Cell Lung Carcinoma Reveals Unique Tumor-Specific Somatic Mutations.

Context.—: Mitochondria and mitochondrial DNA have been suggested to play a role in cancer initiation and progression. Knowledge of mitochondrial DNA could provide a breakthrough to advance cancer management.

Design and Optimization of an α-Helical Bundle Dimer Cell-Penetrating Peptide for Drug Delivery.

To deliver membrane-impermeable drugs into eukaryotic cells, a lot of cell-penetrating peptides (CPPs) were discovered. Previously we designed an amphipathic α-helical peptide which dimerizes itself its two C-residues. This bis-disulfide-linked dimeric bundle, LK-3, has remarkable cell-penetrating ability at nanomolar concentration, which is an essential prerequisite for CPP.

High tumor hexokinase-2 expression promotes a pro-tumorigenic immune microenvironment by modulating CD8+/regulatory T-cell infiltration.

Background: Relationship between cancer cell glycolysis and the landscape of tumor immune microenvironment in human cancers was investigated.

Methods: Forty-one fresh lung adenocarcinoma (ADC) tissues were analyzed using flow cytometry for comprehensive immunoprofiling. Formalin-fixed tissues were immunostained for hexokinase-2 (HK2) to assess cancer cell glycolysis.

TCF1PD-1 tumour-infiltrating lymphocytes predict a favorable response and prolonged survival after immune checkpoint inhibitor therapy for non-small-cell lung cancer.

Background: T-cell factor 1 (TCF1)Programmed cell death-1 (PD-1) tumour-infiltrating lymphocytes (TILs) are a recently defined subset of exhausted T-cells (Texh-cells) that exhibit a progenitor phenotype. They have been associated with a response to immune checkpoint inhibitor (ICI) therapy in murine tumour models and in patients with malignant melanoma. We investigated the significance of TCF1PD-1 TILs as a predictive biomarker for ICI therapy response in non-small-cell lung cancer (NSCLC).

Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells.

Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma.

Histopathologic Basis for a Chest CT Deep Learning Survival Prediction Model in Patients with Lung Adenocarcinoma.

Background A preoperative CT-based deep learning (DL) prediction model was proposed to estimate disease-free survival in patients with resected lung adenocarcinoma. However, the black-box nature of DL hinders interpretation of its results. Purpose To provide histopathologic evidence underpinning the DL survival prediction model and to demonstrate the feasibility of the model in identifying patients with histopathologic risk factors through unsupervised clustering and a series of regression analyses.

OASL1-Mediated Inhibition of Type I IFN Reduces Influenza A Infection-Induced Airway Inflammation by Regulating ILC2s.

Purpose: Three observations drove this study. First, 2'-5'-oligoadenylate synthetase-like protein (OASL) is a negative regulator of type I interferon (IFN). Second, type I IFN plays a central role during virus infections and the pathogenesis of various diseases, including asthma.

A unique population of neutrophils generated by air pollutant-induced lung damage exacerbates airway inflammation.

Background: Diesel exhaust particles (DEPs) are the main component of traffic-related air pollution and have been implicated in the pathogenesis and exacerbation of asthma. However, the mechanism by which DEP exposure aggravates asthma symptoms remains unclear.

Objective: This study aimed to identify a key cellular player of air pollutant-induced asthma exacerbation and development.

Interactions between NCRILC3s and the Microbiome in the Airways Shape Asthma Severity.

Asthma is a heterogeneous disease whose development is shaped by a variety of environmental and genetic factors. While several recent studies suggest that microbial dysbiosis in the gut may promote asthma, little is known about the relationship between the recently discovered lung microbiome and asthma. Innate lymphoid cells (ILCs) have also been shown recently to participate in asthma.

Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells.

Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma.

Ssu72 phosphatase directly binds to ZAP-70, thereby providing fine-tuning of TCR signaling and preventing spontaneous inflammation.

ZAP-70 is required for the initiation of T cell receptor (TCR) signaling, and Ssu72 is a phosphatase that regulates RNA polymerase II activity in the nucleus. However, the mechanism by which ZAP-70 regulates the fine-tuning of TCR signaling remains elusive. Here, we found that Ssu72 contributed to the fine-tuning of TCR signaling by acting as tyrosine phosphatase for ZAP-70.