Editors' ChoiceCancer

Inflammatory signatures of smoking

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Science Translational Medicine  09 May 2018:
Vol. 10, Issue 440, eaat8528
DOI: 10.1126/scitranslmed.aat8528


Smoking is associated with distinct pro- and anti-inflammatory signatures in squamous cell carcinomas of the lung and the head and neck.

Recognition of the importance of the immune system in malignancy is not new. We now have therapies that—by targeting specific immune checkpoint inhibitor molecules—release the brakes on effector T cells and have revolutionized the therapeutic approach to melanoma and lung cancer. The expression of some of these checkpoint inhibitors is associated with smoking status. However, not all smoking-associated cancers behave the same, and some, such as head and neck squamous cell carcinoma, do not respond well to checkpoint inhibition.

Deciphering the role of smoking on the tumor-associated microenvironment is key to the development of personalized treatment approaches. To this end, Desrichard et al. used The Cancer Genome Atlas and two independent gene expression data sets containing RNA and DNA sequencing data from subjects with lung squamous cell carcinoma and head and neck squamous cell carcinoma. The mutational signatures associated with smoking were similar across data sets. However, the clinical response to immunotherapy and genomic signatures of immune activity associated with smoking differed depending on the location of the cancer. In squamous cell carcinoma of the head and neck, smoking was associated with an immunosuppressive tumor environment and poorer outcome. In contrast, in squamous cell carcinoma of the lung, smoking was associated with a more inflammatory profile of the tumor environment and stronger response to checkpoint inhibitor therapy.

The authors argue that smoking has direct immunosuppressive and proapoptotic effects on T cells that might prevail in head and neck cancer. In the lung, however, smoking results in an increased inflammatory tone, especially among patients who develop chronic obstructive pulmonary disease. The opposite directionality of the inflammatory profile associated with smoking in the lung versus head and neck squamous cell carcinomas is mechanistically intriguing, but deciphering the effects of tobacco smoke on the immune tone that affects cancer will require moving beyond cross-sectional human studies.

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