COMMENTARY

Study Suggests Immune Link Between Smoking and Colorectal Cancer

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci

Disclosures

March 27, 2019

This transcript has been edited for clarity.

Hello. I'm David Kerr, professor of cancer medicine at University of Oxford. All of us are interested in the etiologic associations with disease. With colorectal cancer, a number of lifestyle factors are risk-associated. Smoking is one, and while relatively weak, I do counsel all of our patients and their families not to smoke.

Is there any connection between the biology of colorectal cancer and smoking as a risk factor? A recent study by Dr Hamada and colleagues[1] in Journal of the National Cancer Institute tested the hypothesis that smoking might have some detrimental effect on innate immunity, and that might be the biological link between the act of smoking and the biology which is associated with colorectal carcinogenesis. They followed 135,000 patients from the Nurses' Health Study and Health Professionals Follow-up Study, which are very large prospective trials. They now have about 3.5 million years' worth of follow-up. In that very large cohort they found 700 or so cases of colorectal cancer [with available molecular data].

They made a huge effort to collect the paraffin-embedded tissue associated with the cohort and to do all sorts of detailed molecular analysis. They took a rather reductionist approach and looked at CD3 expression as a marker of pan-T cells, markers for regulatory T cells, and other markers, such as CD8 and so on, to see if they could tease out whether there were any subtle biological differences between the different strata of an infiltrating T lymphocyte. They found that those who smoke have lower numbers of infiltrating T lymphocytes. One may hypothesize that they had a diminished immune response.

They had some other hypotheses looking particularly at tumors with microsatellite instability (MSI). We know that these are highly immunogenic tumors. Because of frameshift mutations, they present very large numbers of neoantigens to the body's immune system. We know that they are associated with heavy T-cell lymphocytic infiltrate. In this study it did not look like smoking seemed to have any influence on the T-cell infiltrates in patients with MSI.

It was a large, well-conducted study, but there are one or two caveats, as there always are. They were not able to collect specimens from the total number of tumors [in the study population]. But I thought they did the study carefully, looking at four tumor cores in their microarrays. They had some well-tested antibodies, an excellent laboratory for demonstrating and counting the number of infiltrating T cells. There may be another confounding factor—who knows—but this showed an interesting link between plausible biology and risk for colorectal carcinogenesis—a statistically important risk because so many still smoke.

Have a look at the paper and see what you think. We tell all of our patients to stop smoking. We know that the chemical components of cigarette smoke, that nicotine, can impair the innate immune system (NK cells, T cells, macrophage functions, and so on). Why continue to do something to one's self that impairs the body's own possibility of mounting some sort of immune response—particularly if you are trying to stimulate that with the use of chemotherapy to cause tumor cell necrosis, antigen release, and so on? We have a simple, practical message now: Don't smoke. This is something we would also say as prevention to the family and carers of those who attend a clinic with our patients with colorectal cancer.

Thanks for listening, as always. For the time being, over and out.

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