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

Alisoltani, Arghavan; Qiu, Xinru; Jaroszewski, Lukasz; Sedova, Mayya; Li, Zhanwen; Godzik, Adam

doi:10.1101/2020.03.06.981225

Cited by 3 publications

(3 citation statements)

References 38 publications

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“…These data suggest important yet unexplored roles for B cell phenotypes in immune evolution of LUAD (40). We also noted strikingly high plasma cell fractions among LUADs from smokers, suggesting that plasma cells may play important roles in the pathogenesis of smoking-associated LUAD and its microenvironment (41). Our analysis also pointed to mechanisms by which the myeloid immune microenvironment permits LUAD pathogenesis.…”

Section: Discussionmentioning

confidence: 68%

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Sinjab

Han

Kobayashi

et al. 2020

Preprint

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Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and fourteen multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to the LUADs. LUADs exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs driven by KRAS mutations. T regulatory cell phenotypes are increased in normal tissues with closer proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. Further, the LUAD ecosystem harbors gain of ligand-receptor based interactions involving increased expression of CD24 antigen on epithelial cells and SIGLEC10 on myeloid subsets. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for treatment.

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Section: Discussionmentioning

confidence: 68%

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Sinjab

Han

Kobayashi

et al. 2020

Preprint

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“…Another limitation is that our study focuses on gene expression data: smoking-related effects occur on multiple biological levels, some of which have sex-related differences. In tumor microenvironments, changes in immune cell populations in response to smoking were more pronounced in women than in men (Alisoltani et al, n.d.). DNA methylation shows sex-specific changes in response to smoking (Koo et al 2020).…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, the tissue-specificity of smoking-related differential expression is less fully characterized. Several analyses have examined effects across tissues, but they focus on cancer (Alexandrov et al 2016;Desrichard et al 2018;Alisoltani et al, n.d) and may not extend to healthy tissues.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Assessment of Smoking and Sex Related Effects in Publicly Available Gene Expression Data

Flynn

Chang

Nugent

et al. 2021

Preprint

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Smoking greatly reduces life expectancy in both men and women, but with different patterns of morbidity. After adjusting for smoking history, women have higher risk of respiratory effects and diabetes from smoking, while men show greater mortality from smoking-related cancers. While many smoking-related sex differences have been documented, the underlying molecular mechanisms are not well understood. To date, identification of sex differences in response to smoking has been limited to a small number of studies and the resulting smoking-related effects require further validation. Publicly available gene expression data present a unique opportunity to examine molecular-level sex and smoking effects across many tissues and studies. We performed a systematic search to identify smoking-related studies from healthy tissue samples and found 31 separate studies as well as an additional group of overlapping studies that in total span 2,177 samples and 12 tissues. These samples and studies were overall male-biased. In smoking, while effects appeared to be somewhat tissue-specific and largely autosomal, we identified a small number of genes that were consistently differentially expressed across tissues, including AHRR and GZMH. We also identified one gene, AKR1C3, encoding an aldo-keto reductase, which showed strong opposite direction, smoking-related effects in blood and airway epithelium, with higher expression in airway epithelium and lower expression in blood of smokers versus non-smokers. By contrast, at similar significance thresholds, sex-related effects were entirely sex chromosomal and consistent across tissues, providing evidence of stronger effects of smoking than sex on autosomal expression. Due to sample size limitations, we only examined interaction effects in the largest study, where we identified 30 genes with sex differential effects in response to smoking, only one of which, CAPN9, replicated in a held-out analysis. Overall these results present a comprehensive analysis of smoking-related effects across tissues and an initial examination of sex differential smoking effects in public gene expression data.

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Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

et al. 2021

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Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand–receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Significance: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception. This article is highlighted in the In This Issue feature, p. 2355

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

Cited by 3 publications

References 38 publications

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Comprehensive Assessment of Smoking and Sex Related Effects in Publicly Available Gene Expression Data

Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

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