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Smoking and Certain Mutations Are Risks For Lung Cancer. But Your Immune System’s Ability to Ferret Out Early Cancer May Be Another One, Researchers Find

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Research results reported in the journal Science today add to the evidence that “immunogenetics” likely influences people’s susceptibility to developing lung cancer, especially among smokers.

Differences in immune systems stemming from differences in genes may confer some protection against lung cancer, especially among people who smoke, according to research findings reported today in the journal Science.

Corresponding author Diego Chowell, Ph.D., an assistant professor at the Icahn School of Medicine at Mount Sinai in New York, and a large research team found that differences human leukocyte antigen class II (HLA-II) genes were associated with a protective effect against lung cancer in both current and former smokers using genetic and clinical data from the UK Biobank and FinnGen. The UK Biobank has genetic information on 500,000 people from the United Kingdom. FinnGen has similar information on 350,000 people from Finland.

Diego Chowell, Ph.D.

Diego Chowell, Ph.D.

Results from their analysis of UK Biobank data showed a 18% reduced risk of developing lung cancer among former smokers with the advantageous set of HLA-II genes. In the FinnGen database, the HLA-II protection was seen among current smokers.

“We provide evidence that immunogenetics is also part of the etiology of cancer along with inherited mutations, DNA replication errors, and environmental factors,” Chowell said in an email to Managed Healthcare Executive.

Their research results may also help explain why some smokers develop lung cancer and others don’t. Those who don’t may have immune systems are vigilant and attuned to mutations resulting from smoking.

HLA genes encode the major histocompatibility complex (MHC) molecules that round up and present antigens for recognition and possible destruction by T cells. Researchers have found that differences in HLA genes — and therefore antigen-presenting MHC molecules and T cell activity — are associated with how people respond to HIV and the chances of an infection developing AIDS and the clearance of a hepatitis B infection.

The trail of theories, research and debate about the immune system’s role in detecting and controlling early cancers goes back to the early 20th century. The question this and other studies have attempted to answer is whether some people are less likelihood to develop cancer because their immune systems are adept at finding and defeating early cancers in roughly the same way the immune system locates and fights off pathogens from outside the body while other people’s immune systems are less able to do so, making them more vulnerable to developing cancer.

Immunogenetics”adds a layer to the research by looking at the genes that encode the immune system and account for some of the differences in the immune responses among people.

Chowell and his colleagues describe lung cancer as “an exemplary disease for study of immunosurveillance in cancer” because the lungs are teeming with T cells. Another reason to suspect that the immune system might police lung cancer is the efficacy of the immunotherapy agents against metastatic lung cancer, they said in the Science paper.

This research focused on the heterozygosity of the HLA-II genes. Genes comes in pairs, and each member of the pair is called an allele. When the pair of the alleles are same (like a pair of shoes), the gene is homozygous. When the alleles in the pair differ, the gene is called heterozygous.

In his email to Managed Healthcare Executive, Chowell said heterozygosity in the related set of HLA-I genes have been shown to protective in the context of clinical outcomes in individuals who already have a disease, such as HIV, but not in cancer risk.

The finding that HLA-II, as opposed to HLA-I, seems to be protective was surprising, he said in the email, because “we always think of the interaction between antigens presented by HLA-I molecules and CD8+ T cells as the most critical process in the immune response.”

They found that “maximal heterozygosity” at a group HLA-II locations was associated with a lower risk of developing lung cancer, not at the HLA-I, and that heterozygosity was especially protective at a particular HLA-II location called HLA-DRB1.

Heterozygosity is believed to be advantageous because it results in a more diverse group of MHC molecules to present more antigens to T cells.

“We believe heterozygosity at the HLA locus results in greater diversity of potential early cancer mutations that could be presented to the immune system and therefore greater chance of the immune system recognizing early tumors and eliminating them,” Robert M. Samstein, M.D., Ph.D., wrote in an email to Managed Healthcare Executive. Samstein is one of large number of co-authors of theresearch published in Science and, like Chowell, a researcher at the Icahn School of Medicine at Mount Sinai and a radiation oncologist there.

Robert Samstein, M.D., Ph.D.

Robert Samstein, M.D., Ph.D.

“Basically,” Samstein wrote, “if you have two different HLA alleles (heterozygous) compared with having two of the same HLA alleles (homozygous) you are better able to recognize and eliminate early lung cancers that are developing.”

In addition to analysis of the UK Biobank and FinnGen data, the Science paper includes of results of research that involved mapping the structure of the MHC molecules and “the peptide-binding groove” that had been previously identified as being important in antigen presentation with respect to HIV. These molecular level results were consistent with the population-level results implicating heterozygosity in the HLA-II genes as affording protection from lung cancer.

The protection, though, was limited to current and former smokers and didn’t extend to people who never smoked. That result may have had something to do study design. But there was a third part of this study that looked the mutations and inflammatory responses triggered by smoking. The results show that smoking seems to stir up a proliferation of HLA-II-rich macrophages that present antigens to T cells.

“Smoking is a strong risk factor for lung cancer, thought to be driven by the increased accumulation of mutations that promote cancer development. These same mutations can also be recognized by the immune system and serve as targets for T cell elimination of the cancer,” Samstein wrote in his email.

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