Summary Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

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Background: While the efficacy of Indwelling pleural catheters for palliation of malignant pleural effusions is supported by relatively robust evidence, there is less clarity surrounding the postinsertion management. Methods: The Trustworthy Consensus-Based Statement approach was utilized to develop unbiased, scientifically valid guidance for the management of patients with malignant effusions treated with indwelling pleural catheters. A comprehensive electronic database search of PubMed was performed based on a priori crafted PICO questions (Population/Intervention/Comparator/Outcomes paradigm). Manual searches of the literature were performed to identify additional relevant literature. Dual screenings at the title, abstract, and full-text levels were performed. Identified studies were then assessed for quality based on a combination of validated tools. Appropriateness for data pooling and formation of evidence-based recommendations was assessed using predetermined criteria. All panel members participated in development of the final recommendations utilizing the modified Delphi technique. Results: A total of 7 studies were identified for formal quality assessment, all of which were deemed to have a high risk of bias. There was insufficient evidence to allow for data pooling and formation of any evidence-based recommendations. Panel consensus resulted in 11 ungraded consensus-based recommendations. Conclusion: This manuscript was developed to provide clinicians with guidance on the management of patients with indwelling pleural catheters placed for palliation of malignant pleural effusions. Through a systematic and rigorous process, management suggestions were developed based on the best available evidence with augmentation by expert opinion when necessary. In addition, these guidelines highlight important gaps in knowledge which require further study.

The human bronchial epithelium is composed of multiple, distinct cell types that cooperate to perform functions, such as mucociliary clearance, that defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, the precise effects of this exposure on specific cell types are not well-understood. We used single-cell RNA sequencing to profile bronchial epithelial cells from six never-and six current smokers. Unsupervised analyses identified thirteen cell clusters defined by unique combinations of nineteen distinct gene sets. Expression of a set of toxin metabolism genes localized to ciliated cells from smokers. Smokinginduced airway remodeling was characterized by a loss of club cells and extensive goblet cell hyperplasia. Finally, we identified a novel peri-goblet epithelial subpopulation in smokers that expressed a marker of bronchial premalignant lesions. Our data demonstrates that smoke exposure drives a complex landscape of cellular and molecular alterations in the human bronchial epithelium that may contribute to the onset of smoking-associated lung diseases.The human bronchus is lined with a pseudostratified epithelium that acts as a physical barrier against exposure to harmful environmental insults such as inhaled toxins, allergens, and pathogens 1-2 . The bronchial epithelium is a complex tissue, predominantly composed of ciliated, goblet, club, and basal epithelial cells. These cell types cooperate to perform mucociliary clearance, which is the process that mediates the capture and removal of inhaled substances 1-2 . Goblet cells secrete components of a mucosal lining that entraps inhaled particulate matter, which is propelled out of the airways by mechanical beating of ciliated cells 1-2 . Club cells also perform a secretory function 3 and serve as facultative progenitors 4 , whereas basal cells are multipotent progenitors responsible for normal tissue homeostasis 5-7 . Interplay amongst these cells is required for proper function and long-term maintenance of the bronchial epithelium, but exposure to substances, like tobacco smoke, might alter or injure specific cell types and lead to tissue-wide dysfunction.Inhalation of tobacco smoke exposes the bronchial epithelium to toxins, carcinogens, and free radicals 8-11 , but cellular injuries and abnormalities associated with this exposure are complex and have not been fully characterized. Previous studies have described smoking-induced epithelial changes, such as increased goblet cell numbers [12][13][14] and reduced ciliary length [15][16] . Robust transcriptomic alterations have also been observed in the bronchial epithelium of smokers, involving the up-regulation of genes linked to xenobiotic metabolism and the oxidative stress response 17-18 . Furthermore, it has been reported that a subset of gene expression alterations detected in smokers persists years after smoking cessation 18 . However, the aforementioned transcriptomic studies profiled bronchial tissue in "bulk", masking cell type-s...

Single-cell RNA-Seq reveals smoking-induced bronchial cell type–specific alterations and a novel peri-goblet cell.

Acute exposure to as little as three cigarettes and chronic smoking induce largely concordant changes in airway epithelial gene expression. Differences in short-term and long-term effects of smoking on metallothionein expression and their relationship to lung cancer requires further study given these enzymes' role in the oxidative stress response.

Lung cancer remains the leading cause of cancer-related death in the United States. Cigarette smoking is a well-recognized risk factor for lung cancer, and a sustained elevation of lung cancer risk persists even after smoking cessation. Despite identifiable risk factors, there has been minimal improvement in mortality for patients with lung cancer primarily stemming from diagnosis at a late stage when there are few effective therapeutic options. Early detection of lung cancer and effective screening of high-risk individuals may help improve lung cancer mortality. While low dose computerized tomography (LDCT) screening of high risk smokers has been shown to reduce lung cancer mortality, the high rates of false positives and potential for over-diagnosis have raised questions on how to best implement lung cancer screening. The rapidly evolving field of lung cancer screening and early-detection biomarkers may ultimately improve the ability to diagnose lung cancer in its early stages, identify smokers at highest-risk for this disease, and target chemoprevention strategies. This review aims to provide an overview of the opportunities and challenges related to lung cancer screening, the field of biomarker development for early lung cancer detection, and the future of lung cancer chemoprevention.