Lung squamous cell carcinoma (LUSC) is a highly heterogeneous cancer that is influenced by etiological agents such as tobacco smoke. Accordingly, transfer RNA-derived fragments (tRFs) are implicated in both cancer onset and development and demonstrate the potential to act as targets for cancer treatments and therapies. Therefore, we aimed to characterize tRF expression with respect to LUSC pathogenesis and clinical outcomes. Specifically, we analyzed the effect of tobacco smoke on tRF expression. In order to do so, we extracted tRF read counts from MINTbase v2.0 for 425 primary tumor samples and 36 adjacent normal samples. We analyzed the data in three primary cohorts: (1) all primary tumor samples (425 samples), (2) smoking-induced LUSC primary tumor samples (134 samples), and (3) non-smoking-induced LUSC primary tumor samples (18 samples). Differential expression analysis was performed to examine tRF expression in each of the three cohorts. tRF expression was correlated to clinical variables and patient survival outcomes. We identified unique tRFs in primary tumor samples, smoking-induced LUSC primary tumor samples, and non-smoking-induced LUSC primary tumor samples. In addition, many of these tRFs demonstrated correlations to worse patient survival outcomes. Notably, tRFs in the smoking-induced LUSC and non-smoking-induced LUSC primary tumor cohorts were significantly correlated to clinical variables pertaining to cancer stage and treatment efficacy. We hope that our results will be used to better inform future LUSC diagnostic and therapeutic modalities. Full article

The heterogeneity of lung tumor nodules is reflected in their phenotypic characteristics in radiological images. The radiogenomics field employs quantitative image features combined with transcriptome expression levels to understand tumor heterogeneity molecularly. Due to the different data acquisition techniques for imaging traits and genomic data, establishing meaningful connections poses a challenge. We analyzed 86 image features describing tumor characteristics (such as shape and texture) with the underlying transcriptome and post-transcriptome profiles of 22 lung cancer patients (median age 67.5 years, from 42 to 80 years) to unravel the molecular mechanisms behind tumor phenotypes. As a result, we were able to construct a radiogenomic association map (RAM) linking tumor morphology, shape, texture, and size with gene and miRNA signatures, as well as biological correlates of GO terms and pathways. These indicated possible dependencies between gene and miRNA expression and the evaluated image phenotypes. In particular, the gene ontology processes “regulation of signaling” and “cellular response to organic substance” were shown to be reflected in CT image phenotypes, exhibiting a distinct radiomic signature. Moreover, the gene regulatory networks involving the TFs TAL1, EZH2, and TGFBR2 could reflect how the texture of lung tumors is potentially formed. The combined visualization of transcriptomic and image features suggests that radiogenomic approaches could identify potential image biomarkers for underlying genetic variation, allowing a broader view of the heterogeneity of the tumors. Finally, the proposed methodology could also be adapted to other cancer types to expand our knowledge of the mechanistic interpretability of tumor phenotypes. Full article

The human microbiome is a vast collection of microbial species that exist throughout the human body and regulate various bodily functions and phenomena. Of the microbial species that exist in the human microbiome, those within the archaea domain have not been characterized to the extent of those in more common domains, despite their potential for unique metabolic interaction with host cells. Research has correlated tumoral presence of bacterial microbial species to the development and progression of lung cancer; however, the impacts and influences of archaea in the microbiome remain heavily unexplored. Within the United States lung cancer remains highly fatal, responsible for over 100,000 deaths every year with a 5-year survival rate of roughly 22.9%. This project attempts to investigate specific archaeal species’ correlation to lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) incidence, patient staging, death rates across individuals of varying ages, races, genders, and smoking-statuses, and potential molecular targets associated with archaea microbiome. Archaeal species abundance was assessed across lung tissue samples of 527 LUAD patients, 479 LUSC patients, and 99 healthy individuals. Nine archaeal species were found to be of significantly altered abundance in cancerous samples as compared to normal counterparts, 6 of which are common to both LUAD and LUSC subgroups. Several of these species are of the taxonomic class Thermoprotei or the phylum Euryarchaeota, both known to contain metabolic processes distinct from most bacterial species. Host-microbe metabolic interactions may be responsible for the observed correlation of these species’ abundance with cancer incidence. Significant microbes were correlated to patient gene expression to reveal genes of altered abundance with respect to high and low archaeal presence. With these genes, cellular oncogenic signaling pathways were analyzed for enrichment across cancer and normal samples. In comparing gene expression between LUAD and adjacent normal samples, 2 gene sets were found to be significantly enriched in cancers. In LUSC comparison, 6 sets were significantly enriched in cancer, and 34 were enriched in normals. Microbial counts across healthy and cancerous patients were then used to develop a machine-learning based predictive algorithm, capable of distinguishing lung cancer patients from healthy normal with 99% accuracy. Full article

Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and individuals with COPD are at a higher risk of developing lung cancer. While the underlying mechanism for this risk is not well understood, its major contributing factors have been proposed to include genomic, immune, and microenvironment dysregulation. Here, we review the evidence and significant studies that explore the mechanisms underlying the heightened lung cancer risk in people with COPD. Genetic and epigenetic changes, as well as the aberrant expression of non-coding RNAs, predispose the lung epithelium to carcinogenesis by altering the expression of cancer- and immune-related genes. Oxidative stress generated by tobacco smoking plays a role in reducing genomic integrity, promoting epithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads to abnormal immune responses that promote cancer development, though not all smokers develop lung cancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPD and accumulating damage from oxidative stress that poses a risk for the development of lung cancer. Dysregulation of the lung microenvironment and microbiome contributes to chronic inflammation, which is observed in COPD and known to facilitate cancer initiation in various tumor types. Further, there is a need to better characterize and identify the proportion of individuals with COPD who are at a high risk for developing lung cancer. We evaluate possible novel and individualized screening strategies, including biomarkers identified in genetic studies and exhaled breath condensate analysis. We also discuss the use of corticosteroids and statins as chemopreventive agents to prevent lung cancer. It is crucial that we optimize the current methods for the early detection and management of lung cancer and COPD in order to improve the health outcomes for a large affected population. Full article

Lung cancer is a disease that in recent years has become one of the greatest threats to modern society. Every year there are more and more new cases and the percentage of deaths caused by this type of cancer increases. Despite many studies, scientists are still looking for answers regarding the mechanisms of lung cancer development and progression, with particular emphasis on the role of the immune system. The aim of this literature review was to present the importance of disorders of the immune system and the accompanying changes at the level of cell signaling in the pathogenesis of lung cancer. The collected results showed that in the process of immunopathogenesis of almost all subtypes of lung cancer, changes in the tumor microenvironment, deregulation of immune checkpoints and abnormalities in cell signaling pathways are involved, which contribute to the multistage and multifaceted carcinogenesis of this type of cancer. We, therefore, suggest that in future studies, researchers should focus on a detailed analysis of tumor microenvironmental immune checkpoints, and to validate their validity, perform genetic polymorphism analyses in a wide range of patients and healthy individuals to determine the genetic susceptibility to lung cancer development. In addition, further research related to the analysis of the tumor microenvironment; immune system disorders, with a particular emphasis on immunological checkpoints and genetic differences may contribute to the development of new personalized therapies that improve the prognosis of patients. Full article

The striking clinical outcomes of antibody-based immunotherapy, through the inhibitors of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and the programmed cell death protein-1 (PD-1) and its ligand (PD-L1) axis, have driven research aimed at identifying further clinically relevant tumor antigens that can serve as targets in solid tumors. B7 homolog 3 protein (B7-H3, also known as CD276) is a member of the B7 family overexpressed in tumor tissues, including non-small cell lung cancer (NSCLC), while showing limited expression in normal tissues, becoming an attractive and promising target for cancer immunotherapy. B7-H3 expression in tumors has been demonstrated to be associated with poor prognosis. In addition to its role in immune modulation, B7-H3 also promotes pro-tumorigenic functions such as tumor migration, invasion, metastases, resistance, and metabolism. In this review, we will provide an overview of this newly characterized immune checkpoint molecule and its development in the management of metastatic NSCLC. Full article