Smoker and non-smoker lung adenocarcinoma is characterized by distinct tumor immune microenvironments

Abstract

Tobacco smoking causes DNA damages in epithelial cells and immune dysfunction in the lung, which collectively contribute to lung carcinogenesis and progression. However, potential mechanisms by which tumor-infiltrating immune cells contribute to lung cancer survival and their differential contributions in ever-smokers and never-smokers are not well studied. Here, we performed integrative analysis of 11 lung cancer gene-expression datasets, including 1,111 lung adenocarcinomas and 200 adjacent normal lung samples. Distinct pathways were altered in lung carcinogenesis in ever-smokers and never-smokers. Never-smoker patients had a better outcome than ever-smoker patients. We characterized compositional patterns of 21 types of immune cells in lung adenocarcinomas and revealed the complex association between immune cell composition and clinical outcomes. Interestingly, we found two subsets of immune cells, mast cells and CD4+ memory T cells, which had completely opposite associations with outcomes in resting and activated status. We further discovered that several chemokines and their associated receptors (e.g., CXCL11-CX3CR1 axis) were selectively altered in lung tumors in response to cigarette smoking and their abundances showed stronger correlation with fractions of these immune subsets in ever-smokers than never-smokers. The status switched from the resting to activated forms in mast cells and CD4+ memory T cells might manifest some important processes induced by cigarette smoking during tumor development and progression. Our findings suggested that aberrant activation of mast cells and CD4+ memory T cells plays crucial roles in cigarette smoking-induced immune dysfunction in the lung, which contributes to tumor development and progression.

The construction and analysis of tumor-infiltrating immune cells and ceRNA networks in metastatic adrenal cortical carcinoma

“…Tumor growth was mainly controlled by CD4 and CD8 T cells [43]. Previous studies had found that T cells CD4+ memory were significantly correlated with the abundance of CCL5-related chemokine receptors [15]. CCL5 might induce the recruitment and activation of specific memory T cells by interacting with certain receptors on memory T cells [15].…”

“…CCL5 might induce the recruitment and activation of specific memory T cells by interacting with certain receptors on memory T cells [15]. CCR5 was the most famous receptor of CCL5 [15]. Previous studies had also shown that the CCL5-CCR5 axis played an active role in the tumorigenesis: as a growth factor, it stimulated angiogenesis and participated in the immune escape mechanism [44].…”

“…Only bilateral P < 0.05 was considered statistically significant. Institute of Statistics and Mathematics, Vienna, Austria (Package: GDCRNATools [15], edgeR, ggplot2, RMS, planet, preprocessCore, curvilinear, timeROC).…”

Large scale analysis of smoking-induced changes in the tumor immune microenvironment

“…At the same time, tobacco smoking has a well-recognized impact on the function of both innate and adaptive immunity, including that in cancer 4 . Specific changes observed included high white blood cell counts; high counts of cytotoxic or suppressor T cells, low counts of inducer or helper T cells, slight suppression of T-lymphocyte activity, significantly lower activity of natural killer cells, and overall increased susceptibility to infection 5 .…”

“…2c, d). Interestingly, Li et al 4 reported the opposite status of resting to activated mast cells in smokers. We also identified significant changes in the quantity of other innate immunity elements such as dendritic cells, eosinophils, macrophages, and neutrophils, in smokers (Fig.…”