Soluble biomarkers to predict clinical outcomes in non-small cell lung cancer treated by immune checkpoints inhibitors.

peer reviewedLung cancer remains the first cause of cancer-related death despite many therapeutic innovations, including immune checkpoint inhibitors (ICI). ICI are now well used in daily practice at late metastatic stages and locally advanced stages after a chemo-radiation. ICI are also emerging in the peri-operative context. However, all patients do not benefit from ICI and even suffer from additional immune side effects. A current challenge remains to identify patients eligible for ICI and benefiting from these drugs. Currently, the prediction of ICI response is only supported by Programmed death-ligand 1 (PD-L1) tumor expression with perfectible results and limitations inherent to tumor-biopsy specimen analysis. Here, we reviewed alternative markers based on liquid biopsy and focused on the most promising biomarkers to modify clinical practice, including non-tumoral blood cell count such as absolute neutrophil counts, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, and derived neutrophil to lymphocyte ratio. We also discussed soluble-derived immune checkpoint-related products such as sPD-L1, circulating tumor cells (detection, count, and marker expression), and circulating tumor DNA-related products. Finally, we explored perspectives for liquid biopsies in the immune landscape and discussed how they could be implemented into lung cancer management with a potential biological-driven decision

ZO-1 Intracellular Localization Organizes Immune Response in Non-Small Cell Lung Cancer

International audienceDelocalization of zonula occludens-1 (ZO-1) from tight junctions plays a substantial role in epithelial cell plasticity observed during tumor progression. In vitro , we reported an impact of ZO-1 cyto-nuclear content in modulating the secretion of several pro-inflammatory chemokines. In vivo , we demonstrated that it promotes the recruitment of immune cells in mouse ear sponge assays. Examining lung cancers, we showed that a high density of CD8 cytotoxic T cells and Foxp3 immunosuppressive regulatory T cells in the tumor microenvironment correlated with a cyto-nuclear expression of ZO-1. Taken together, our results support that, by affecting tumor cell secretome, the cyto-nuclear ZO-1 pool may recruit immune cells, which could be permissive for tumor progression

Hypoxia in Lung Cancer Management: A Translational Approach

SIMPLE SUMMARY: Hypoxia is a common feature of lung cancers. Nonetheless, no guidelines have been established to integrate hypoxia-associated biomarkers in patient management. Here, we discuss the current knowledge and provide translational novel considerations regarding its clinical detection and targeting to improve the outcome of patients with non-small-cell lung carcinoma of all stages. ABSTRACT: Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management

Soluble biomarkers to predict clinical outcomes in non-small cell lung cancer treated by immune checkpoints inhibitors

Lung cancer remains the first cause of cancer-related death despite many therapeutic innovations, including immune checkpoint inhibitors (ICI). ICI are now well used in daily practice at late metastatic stages and locally advanced stages after a chemo-radiation. ICI are also emerging in the peri-operative context. However, all patients do not benefit from ICI and even suffer from additional immune side effects. A current challenge remains to identify patients eligible for ICI and benefiting from these drugs. Currently, the prediction of ICI response is only supported by Programmed death-ligand 1 (PD-L1) tumor expression with perfectible results and limitations inherent to tumor-biopsy specimen analysis. Here, we reviewed alternative markers based on liquid biopsy and focused on the most promising biomarkers to modify clinical practice, including non-tumoral blood cell count such as absolute neutrophil counts, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, and derived neutrophil to lymphocyte ratio. We also discussed soluble-derived immune checkpoint-related products such as sPD-L1, circulating tumor cells (detection, count, and marker expression), and circulating tumor DNA-related products. Finally, we explored perspectives for liquid biopsies in the immune landscape and discussed how they could be implemented into lung cancer management with a potential biological–driven decision

Plasticité phénotypique et thérapies ciblées dans les cancers bronchiques non à petites cellules

International audienceLung cancer is the most diagnosed and deathly type of cancer worldwide. It has a poor prognosis because of a late diagnosis, high metastatic potential and resistance to conventional therapies. Since the 2000s, the emergence of targeted therapies has improved patients' outcomes. However, these therapies concern only a small proportion of patients, selected by the presence of molecular biomarkers that indicate the targeting relevance. Here, we discuss the possibility that new phenotypical biomarkers could be predictive factors for targeted therapies in lung cancer.Le cancer bronchique représente la première cause de décès par cancer dans le monde. Il est de mauvais pronostic avec un diagnostic tardif, un fort potentiel métastatique et une résistance aux thérapies conventionnelles. Depuis les années 2000, l'apparition des thérapies ciblées a permis d'améliorer le pronostic des patients. Cependant, ces thérapies ne s'adressent qu'à une faible proportion de patients, sélectionnés par la présence d'un biomarqueur moléculaire qui indiquera que le ciblage est pertinent. Ici, nous discutons de la possibilité d'utiliser de nouveaux biomarqueurs phénotypiques comme facteurs prédictifs de réponse aux thérapies ciblées dans les cancers bronchiques non à petites cellules

Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis.

Cystic fibrosis (CF) at an advanced stage of the disease is characterized by airway epithelial injury and remodelling. Whether CF remodelling is related to infection and inflammation or due to an abnormal regenerative process is still undecided. We have recently established the expression and secretion profiles of interleukin (IL)-8, matrix metalloproteinase (MMP)-7, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 during non-CF airway epithelial regeneration in a humanized nude mouse xenograft model. To enhance our understanding of CF remodelling, we compared the regeneration process of non-infected human CF and non-CF nasal epithelia. In both CF and non-CF situations, epithelial regeneration was characterized by successive steps of cell adhesion and migration, proliferation, pseudostratification, and terminal differentiation. However, histological examination of the grafts showed a delay in differentiation of the CF airway epithelium. Cell proliferation was higher in the regenerating CF epithelium, and the differentiated CF epithelium exhibited a pronounced height increase and basal cell hyperplasia in comparison with non-CF epithelium. In addition, while the number of goblet cells expressing MUC5AC was similar in CF and non-CF regenerated epithelia, the number of MUC5B-immunopositive goblet cells was lower in CF grafts. The expression of human IL-8, MMP-7, MMP-9, and TIMP-1 was enhanced in CF epithelium, especially early in the regenerative process. Together, our data strongly suggest that the regeneration of human CF airway surface epithelium is characterized by remodelling, delayed differentiation, and altered pro-inflammatory and MMP responses

A density-based cellular automaton model for studying the clustering of noninvasive cells.

We investigated whether cluster formation by noninvasive cells can be explained by a global attractive potential. Indices quantifying the persistence of migration in experimental conditions were compared to the same indexes computed from simulations with a density-based cellular automaton. The results indicate that the attractive potential hypothesis must be rejected

Cell migration and proliferation are not discriminatory factors in the in vitro sociologic behavior of bronchial epithelial cell lines.

A model of cellular cohesion has been developed, which permits the in vitro study of the spatial and temporal distribution of two human bronchial cell lines. The spatial distribution of cells in culture was characterized from videomicroscopic recordings and analyzed using an algorithmic program of cellular sociology based on the use of three geometrical models: Vorono? partition, Delaunay's graph, the and minimum spanning tree (MST). The results obtained suggested that the manner of cellular cohesiveness could be used to differentiate between the organizational behaviors of the cell lines: non-invasive 16HBE14o- cells rapidly formed clusters with a cohesive organization, whereas invasive BZR cells remained isolated and were characterized by a non-cohesive organization. Videomicroscopic and image analysis techniques also demonstrated that cell migration and proliferation are not discriminatory factors for explaining differences in the spatial organizations of the two cell lines. We concluded that the random nature of cell movement combined with the cell adhesion capacity are determinant factors in cell cluster formation

A density-based cellular automaton model for studying the clustering of noninvasive cells.

We investigated whether cluster formation by noninvasive cells can be explained by a global attractive potential. Indices quantifying the persistence of migration in experimental conditions were compared to the same indexes computed from simulations with a density-based cellular automaton. The results indicate that the attractive potential hypothesis must be rejected