Lung cancer is the leading cancer killer worldwide, imposing grievous challenges for patients and clinicians. The incidence of lung adenocarcinoma (LUAD), the main histologic subtype of lung cancer, is still increasing in current-, ex-, and even non-smokers, whereas its five-year survival rate is approximately 15% as the vast majority of patients usually present with advanced disease at the time of diagnosis. The generation of novel drugs targeting key disease driver mutations has created optimism for the treatment of LUAD, but, as these mutations are not universal, this therapeutic line benefits only a subset of patients. More recently, the advent of targeted immunotherapies and their documented clinical efficacy in many different cancers, including LUAD, have started to change cancer management. Immunotherapies have been developed in order to overcome the cancer’s ability to develop mechanisms of immune resistance, i.e., to adapt to and evade the host inflammatory and immune responses. Identifying a cancer’s immune resistance mechanisms will likely advance the development of personalized immunotherapies. This review examines the key pathways of immune resistance at play in LUAD and explores therapeutic strategies which can unleash potent antitumor immune responses and significantly improve therapeutic efficacy, quality of life, and survival in LUAD.

Lung cancer and chronic lung diseases impose major disease burdens worldwide and are caused by inhaled noxious agents including tobacco smoke. The cellular origins of environmental-induced lung tumors and of the dysfunctional airway and alveolar epithelial turnover observed with chronic lung diseases are unknown. To address this, we combined mouse models of genetic labeling and ablation of airway (club) and alveolar cells with exposure to environmental noxious and carcinogenic agents. Club cells are shown to survive KRAS mutations and to form lung tumors after tobacco carcinogen exposure. Increasing numbers of club cells are found in the alveoli with aging and after lung injury, but go undetected since they express alveolar proteins. Ablation of club cells prevents chemical lung tumors and causes alveolar destruction in adult mice. Hence club cells are important in alveolar maintenance and carcinogenesis and may be a therapeutic target against premalignancy and chronic lung disease.

The lungs are frequently affected by cancer metastasis. Although NRAS mutations have been associated with metastatic potential, their exact role in lung homing is incompletely understood. We cross‐examined the genotype of various tumor cells with their ability for automatic pulmonary dissemination, modulated NRAS expression using RNA interference and NRAS overexpression, identified NRAS signaling partners by microarray, and validated them using Cxcr1‐ and Cxcr2‐deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressed NRAS promotes lung colonization by regulating interleukin‐8‐related chemokine expression, thereby initiating interactions between tumor cells, the pulmonary vasculature, and myeloid cells. Our results support a model where NRAS‐mutant, chemokine‐expressing circulating tumor cells target the CXCR1‐expressing lung vasculature and recruit CXCR2‐expressing myeloid cells to initiate metastasis. We further describe a clinically relevant approach to prevent NRAS‐driven pulmonary metastasis by inhibiting chemokine signaling. In conclusion, NRAS promotes the colonization of the lungs by various tumor types in mouse models. IL‐8‐related chemokines, NRAS signaling partners in this process, may constitute an important therapeutic target against pulmonary involvement by cancers of other organs. Synopsis Mutations in the NRAS oncogene are shown to promote lung metastasis by regulating chemokine expression in tumor cells and hence their affinity for the pulmonary vasculature and their ability to form metastatic niches. NRAS mutations and/or gain promote lung metastasis of circulating tumor cells. NRAS promotes interleukin‐8‐related chemokine secretion by tumor cells. Chemokines signal to CXCR1 and CXCR2 receptors on lung endothelial and bone marrow cells to initiate metastatic niches in the lungs. Inhibition of CXCR1 and/or CXCR2 signaling inhibits lung metastasis in mouse models. NRAS gain‐of‐function is correlated with the presence of pulmonary metastases in a meta‐analysis of a large autopsy study using contemporary genomic data from COSMIC.

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1 , NF2 , CDKN2A , and TP53 , but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRAS ^G12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRAS ^G12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.

Switching off malignant pleural effusion formation—fantasy or future?

Epigenetic approaches in direct correlation with assessment of critical genetic mutations in non-small cell lung cancer (NSCLC) are currently very intensive, as the epigenetic components underlying NSCLC development and progression have attained high recognition. In this level of research, established human NSCLC cell lines as well as experimental animals are widely used to detect novel biomarkers and pharmacological targets to treat NSCLC. The epigenetic background holds a great potential for the identification of epi-biomarkers for treatment response however, it is highly complex and requires precise definition as these phenomena are variable between NSCLC subtypes and systems origin.