Treatment of NSCLC after chemoimmunotherapy - are we making headway?

The treatment landscape of non-small-cell lung cancer (NSCLC) has evolved considerably with the integration of immune-checkpoint inhibitors (ICIs) into first-line regimens. However, the majority of patients will ultimately have primary resistance or develop secondary resistance, driven by a complex interplay of intrinsic tumour biology and adaptive changes within the tumour microenvironment (TME), which can be further amplified by host-related factors such as dysbiosis and organ-specific conditions. Despite these heterogeneous origins, most mechanisms of resistance to ICIs lead to an immunosuppressive TME as the final common pathway.

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: results of the NEOMUN trial.

Background: The phase II NEOMUN trial was conducted to investigate the therapeutic effect of preoperative programmed death receptor-1 inhibitor pembrolizumab for treating non-small cell lung cancer (NSCLC). Herein, we report the final efficacy, safety, and long-term survival results.

Methods: Patients with resectable stage II/IIIA NSCLC were included.

Living human lung slices for ex vivo modelling of lung cancer.

The tumor microenvironment (TME) markedly affects cancer progression, yet traditional animal models do not fully recapitulate the situation in humans. To address this, we developed tumor-derived precision lung slices (TD-PCLS), an ex vivo platform for studying the lung TME and evaluating therapies. TD-PCLS, viable for 8-10 days, preserve the heterogeneity and metabolic activity of primary tumors, as confirmed by seahorse analysis.

Macrophage fatty acid metabolism under chronic hypoxia shapes γδ T cell recruitment via CCL22.

Hypoxia in solid tumors is associated with poor outcomes because of metabolic adaptations that support tumor cell survival and alter immune cell function. However, the metabolic and phenotypic adaptations of macrophages (MФs) to chronic hypoxia (CH) remain unclear. This study identifies impaired activity of the oxygen-dependent enzyme stearoyl-CoA desaturase 1 (SCD1) as a driver of altered fatty acid (FA) metabolism in MФs under CH.

Transcriptomic profiling of granuloma in patients with cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is an inflammatory condition characterized by the accumulation and clustering of immune cells, primarily macrophages, leading to granuloma formation. Despite its clinical significance, CS remains relatively understudied, particularly concerning the molecular mechanisms driving fibrosis and disease progression. To explore potential therapeutic targets, we aimed to characterize the transcriptomic landscape of CS granulomas.

RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α.

Defective DNA repair and metabolic rewiring are highly intertwined in promoting the development and progression of cancer. However, the molecular players at their interface remain poorly understood. Here we show that an RNF20-HIF1α axis links the DNA damage response and metabolic reprogramming in lung cancer.

Lung tumor immunity: redirecting macrophages through infection-induced inflammation.

Macrophages play a central role in maintaining tissue homeostasis and in surveillance against pathogens and disease. In the lung, they can adopt either proinflammatory or anti-inflammatory states depending on the nature of the stimulus. As the predominant immune cells in both the lung tumor microenvironment and in sites of lung infection, the functional plasticity of macrophages makes them key players in determining disease outcome.

Cell type-specific efferocytosis determines functional plasticity of alveolar macrophages.

Resolution of lung injuries is vital to maintain gas exchange, but there is an increased risk of secondary bacterial infections during this stage. Alveolar macrophages (AMs) are crucial to clear bacteria and control the resolution of inflammation, but environmental cues that switch functional phenotypes of AMs remain incompletely understood. Here, we found that AMs lack the capacity to mount an effective immune response against bacteria during resolution of inflammation.

Echocardiographic Measure of Right Ventricular-Pulmonary Arterial Coupling Predicts Survival in Lung Cancer.

Echocardiographic indicators of pulmonary hypertension have been reported to predict decreased survival in patients with lung cancer. We tested the hypothesis that this may be associated with impaired right ventricular (RV)-systolic pulmonary arterial pressure (sPAP) coupling. This prospective observational study included 220 outpatients with non-small cell lung cancer examined using Doppler, strain, and three-dimensional echocardiography before starting therapy.

Host Plasma Microenvironment in Immunometabolically Impaired HIV Infection Leads to Dysregulated Monocyte Function and Synaptic Transmission Ex Vivo.

Risk stratification using multi-omics data deepens understanding of immunometabolism in successfully treated people with HIV (PWH) is inadequately explained. A personalized medicine approach integrating blood cell transcriptomics, plasma proteomics, and metabolomics is employed to identify the mechanisms of immunometabolic complications in prolonged treated PWH from the COCOMO cohort. Among the PWHs, 44% of PWH are at risk of experiencing immunometabolic complications identified using the network-based patient stratification method.

Decoding lysosome communication.

Lysosome interaction with other organelles may be linked to pulmonary hypertension.

Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations.

The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells.

Impact of T Cell Ratios on Survival in Pleural Mesothelioma: Insights from Tumor Microenvironment Analysis.

Immunotherapy has significantly improved overall survival in patients with pleural mesothelioma, yet this benefit does not extend to those with the epithelioid subtype. Tumor growth is believed to be influenced by the immune response. This study aimed to analyze the tumor microenvironment to gain a better understanding of its influence on tumor growth.

RUNX1 interacts with lncRNA SMANTIS to regulate monocytic cell functions.

Monocytes, the circulating macrophage precursors, contribute to diseases like atherosclerosis and asthma. Long non-coding RNAs (lncRNAs) have been shown to modulate the phenotype and inflammatory capacity of monocytes. We previously discovered the lncRNA SMANTIS, which contributes to cellular phenotype expression by controlling BRG1 in mesenchymal cells.

Imperative role of adaptor proteins in macrophage toll-like receptor signaling pathways.

Macrophages are integral part of the body's defense against pathogens and serve as vital regulators of inflammation. Adaptor molecules, featuring diverse domains, intricately orchestrate the recruitment and transmission of inflammatory responses through signaling cascades. Key domains involved in macrophage polarization include Toll-like receptors (TLRs), Src Homology2 (SH2) and other small domains, alongside receptor tyrosine kinases, crucial for pathway activation.

CRISPR/Cas-Mediated Knockdown of PD-L1 and KRAS in Lung Cancer Cells.

Cancer cells can escape death and surveillance by the host immune system in various ways. Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed by most cell types, including cancer cells, and can provide an inhibitory signal to its receptor PD-1, which is expressed on the surface of activated T cells, impairing the immune response. PD-L1/PD-1-mediated immune evasion is observed in several KRAS-mutated cancers.

Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension.

Right ventricular (RV) function is critical to prognosis in all forms of pulmonary hypertension. Here we perform molecular phenotyping of RV remodeling by transcriptome analysis of RV tissue obtained from 40 individuals, and two animal models of RV dysfunction of both sexes. Our unsupervised clustering analysis identified 'early' and 'late' subgroups within compensated and decompensated states, characterized by the expression of distinct signaling pathways, while fatty acid metabolism and estrogen response appeared to underlie sex-specific differences in RV adaptation.

Non-invasive surrogate markers of pulmonary hypertension are associated with poor survival in patients with cancer.

Background: Cancer is one of the leading causes of death worldwide, and cardiopulmonary comorbidities may further adversely affect cancer prognosis. We recently described lung cancer-associated pulmonary hypertension (PH) as a new form of PH and comorbidity of lung cancer. While patients with lung cancer with PH had significantly reduced overall survival compared with patients without PH, the prevalence and impact of PH in other cancers remain unclear.

Sanglifehrin A mitigates multiorgan fibrosis by targeting the collagen chaperone cyclophilin B.

Pathological deposition and crosslinking of collagen type I by activated myofibroblasts drives progressive tissue fibrosis. Therapies that inhibit collagen synthesis have potential as antifibrotic agents. We identify the collagen chaperone cyclophilin B as a major cellular target of the natural product sanglifehrin A (SfA) using photoaffinity labeling and chemical proteomics.

SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF.

Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD)-dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF).

KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma.

Background: Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information.

Methods: The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations.

Endothelin and the tumor microenvironment: a finger in every pie.

The tumor microenvironment (TME) plays a central role in the development of cancer. Within this complex milieu, the endothelin (ET) system plays a key role by triggering epithelial-to-mesenchymal transition, causing degradation of the extracellular matrix and modulating hypoxia response, cell proliferation, composition, and activation. These multiple effects of the ET system on cancer progression have prompted numerous preclinical studies targeting the ET system with promising results, leading to considerable optimism for subsequent clinical trials.

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look.

Macrophages play a central role in initiating, maintaining, and terminating inflammation. For that, macrophages respond to various external stimuli in changing environments through signaling pathways that are tightly regulated and interconnected. This process involves, among others, autoregulatory loops that activate and deactivate macrophages through various cytokines, stimulants, and other chemical mediators.

miR-147b mediated suppression of DUSP8 promotes lung cancer progression.

Dual-specificity phosphatase 8 (DUSP8) plays an important role as a selective c-Jun N-terminal kinase (JNK) phosphatase in mitogen-activated protein kinase (MAPK) signaling. In this study, we found that DUSP8 is silenced by miR-147b in patients with lung adenocarcinoma (LUAD), which correlates with poor overall survival. Overexpression of DUSP8 resulted in a tumor-suppressive phenotype in vitro and in vivo experimental models, whereas silencing DUSP8 with a siRNA approach abrogated the tumor-suppressive properties.