Emerging Roles of the Host Immune Contexture and Microenvironment in the Early Pathogenesis of Lung CancerSubmit Manuscript on this topic
The dynamic relationship between tumor cells and immune microenvironment plays key roles in lung cancer pathogenesis. This interplay often involves failure of deployment of cytotoxic T-cell lymphocytes (CTLs) that can target tumor cells, and induction of a pro-tumor/immune-suppressive inflammatory microenvironment. Tumor-promoting inflammation is a major hallmark of lung cancer. Mutant (transformed) lung epithelial cells produce various cytokines and chemokines that attract leukocytes.
Leukocytes can amplify epithelial innate immune responses by initiating a secondary wave of anti- or pro-tumor immune response (intrinsic inflammation). Markers of the immune response are prognostic and predictive in lung adenocarcinoma (LUAD) patients; for example, increased levels of tumor-infiltrating CTLs are a favorable prognostic indicator, and on the contrary, macrophage infiltration is associated with a poor prognosis and reduced survival. The relationship between cigarette smoking and chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, serves as a paradigm for the interdependency of oncogenic transformation and inflammation in lung tumorigenesis.
Smokers with COPD have an increased risk of lung cancer compared to smokers with comparable cigarette exposure but without COPD. Importantly, among smokers with COPD, even following smoking cessation, inflammation persists as does the increased risk of lung cancer. These observations suggest a strong link between COPD-related inflammation (extrinsic inflammation) and lung cancer independent of smoking. Yet, the exact mechanistic interaction between intrinsic oncogene-driven inflammation and/or extrinsic COPD-related inflammation and the immuno-editing process necessary to escape immunosurveillance into tumor promotion and progression in early phases of lung cancer development are still not well understood. Major immune checkpoint pathways suppressing CTLs function comprise the programmed death ligand 1 (PD-L1), its receptor PD-1, and CTLA-4. Strategies to target these immune checkpoints have become the cornerstone of immunotherapy, and have shown durable responses in patients with “immunogenic” tumors, particularly melanomas and LUADs in smokers.
Studies have shown that a high mutation burden, likely to be caused by carcinogens such as cigarette smoking, is linked to increased immunogenicity and response to immune checkpoint blockers (ICB). Of note, tumoral expression of PD-L1 is positively correlated with somatic mutation burden in LUAD. Also, tumor expression of PD-L1 is associated with response to antibodies against PD-L1 or PD-1. Despite these insights, it is not clear how immune surveillance mechanisms may be altered early in lung cancer pathogenesis. It is not also clear whether COPD in lung cancer patients impacts response to immune checkpoint inhibitors. In this research topic, we propose to provide new and existing data dissecting the cell-type specific mechanistic roles of the host immune contexture and its interplay with tumor/epithelial cells in the early pathogenesis of lung cancer. Also, the topic will discuss immunogenomics of lung cancer with an emphasis on early phases in the disease including preneoplasia. We will also review the functional and translational significance of targeting these immune-based pathways for prevention and early treatment of lung malignancy. In addition, we will discuss the potential of combining novel immune-based modalities to improve the efficacy of currently available treatment regimens including ICB in lung cancer.
In this Research Topic, we welcome the submission of Original Research, Review, Methods, Protocols and Hypothesis and Theory articles covering, but not limited to, the following topics:
• New and existing data dissecting the cell-type specific mechanistic roles of the host immune contexture and its interplay with tumor/epithelial cells in the early pathogenesis of lung cancer.
• Immunogenomics of lung cancer with an emphasis on early phases in the disease.
• The functional and translational significance of targeting these immune-based pathways for prevention and early treatment of lung malignancy.
• Combination strategies of immune-based modalities to improve the efficacy of other available treatment regimens in lung cancer.