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Published on: April 22, 2019
Tobacco Smoking-Associated Alterations in the Immune Microenvironment of Squamous Cell Carcinomas
Alexis Desrichard1,2, Fengshen Kuo1, Diego Chowell1,2
1Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY.
Background:
Tobacco smoking creates DNA damage, inducing mutations and potentially altering the tumor immune microenvironment. These types of genetic and immune microenvironment alterations are critical factors known to affect tumor response to immunotherapy. Here we analyze the association between the mutational signature of tobacco smoking, tumor mutational load, and metrics of immune activity in squamous cell carcinomas arising in the head and neck and lung.
Methods:
Using RNA and DNA sequencing data from The Cancer Genome Atlas head and neck (HNSC; n = 287) and lung (LUSC; n = 130) squamous cell carcinoma data sets and two independent gene expression data sets (HNSC, n = 136; LUSC, n = 75), we examined associations between the mutational smoking signature, mutation count, immune cell infiltration, cytolytic activity, and interferon-γ signaling.
Results:
An increasing mutational smoking signature was associated with statistically significantly increased overall mutational load in both HNSC (ρ = .33, P = 1.01 × 10-7) and LUSC (ρ = .49, P = 2.80 × 10-9). In HNSC, a higher mutational smoking signature was associated with lower levels of immune infiltration (ρ = -.37, P = 1.29 × 10-10), cytolytic activity (ρ = -.28, P = 4.07 × 10-6), and interferon-γ pathway signaling (ρ = .39, P = 3.20 × 10-11). In LUSC, these associations were reversed (ρ = .19, P = .03; ρ = .20, P = .02; and ρ = .18, P = .047, respectively). Differentially expressed genes between smoking-high and smoking-low tumors revealed broad tobacco-induced immunosuppression in HNSC, in contrast to a tumor-inflamed microenvironment in smokers with LUSC.
Conclusions:
In squamous cell carcinomas, the genetic smoking signature is associated with higher mutational load, but variable effects on tumor immunity can occur, depending on anatomic site. In HNSC, smoking is predominantly immunosuppressive; in LUSC, more pro-inflammatory. Both tumor mutation load and immune microenvironment affect clinical response to immunotherapy. Thus, the mutational smoking signature is likely to have relevance for immunotherapeutic investigation in smoking-associated cancers.
Insights
Tobacco smoking’s DNA damage signature increases tumor mutational load. However, it causes immunosuppression in head and neck squamous cell carcinomas but promotes inflammation in lung squamous cell carcinomas, impacting immunotherapy response.
Area of Science:
- Oncology
- Cancer Genomics
- Immunology
Background:
- Tobacco smoking induces DNA damage, leading to mutations and alterations in the tumor immune microenvironment.
- These genetic and immune changes are crucial factors influencing a tumor's response to immunotherapy.
- The study investigates the link between smoking-induced mutational signatures, tumor mutational burden, and immune activity in head and neck and lung squamous cell carcinomas.
Purpose of the Study:
- To analyze the association between the mutational signature of tobacco smoking and tumor mutational load.
- To examine the relationship between the smoking signature, mutation count, and immune activity metrics.
- To understand how smoking impacts the tumor immune microenvironment in different cancer types.
Main Methods:
- Utilized RNA and DNA sequencing data from The Cancer Genome Atlas (TCGA) for head and neck (HNSC) and lung (LUSC) squamous cell carcinomas.
- Analyzed two independent gene expression datasets for HNSC and LUSC.
- Investigated associations between the smoking mutational signature, mutation count, immune cell infiltration, cytolytic activity, and interferon-gamma signaling.
Main Results:
- An increasing mutational smoking signature correlated with significantly higher overall mutational load in both HNSC and LUSC.
- In HNSC, a higher smoking signature was linked to reduced immune infiltration, cytolytic activity, and interferon-gamma signaling.
- Conversely, in LUSC, a higher smoking signature was associated with increased immune infiltration, cytolytic activity, and interferon-gamma signaling, indicating site-specific immune responses.
Conclusions:
- The genetic smoking signature is linked to increased mutational load in squamous cell carcinomas, but its effect on tumor immunity varies by anatomic site.
- Smoking predominantly causes immunosuppression in head and neck cancers, while promoting a pro-inflammatory tumor microenvironment in lung cancers.
- Given that both tumor mutation load and immune microenvironment affect immunotherapy response, the smoking mutational signature is relevant for investigating immunotherapies in smoking-associated cancers.
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