ľ�ϸ���Ӱ��

COVID-19 can trigger inflammation that can awaken dormant cancer cells in the lungs, raising the risk of lung metastasis and cancer-related death. This was revealed by research conducted by an international team of top researchers, published today in the journal Nature. Roel Vermeulen led the epidemiological part of the study. KWF Dutch Cancer Society will be funding follow research by Vermeulen.

The effects of the SARS-CoV2 virus on the elderly and people with compromised immune systems is by now well-documented, but new research reveals another group that could be affected by COVID infection — cancer patients, in particular cancer patients whose disease has gone into remission. 

The study was led by ľ�ϸ���Ӱ�� of Colorado Cancer Center Deputy Director James DeGregori. Key collaborators include investigators in New York, led by Julio Aguirre-Ghiso (Albert Einstein College of Medicine), and in Europe, led by Roel Vermeulen. “This complex and multidisciplinary study truly took a village,” DeGregori says.

Fuel on the fire

It is known that people who are treated for their cancers can remain disease free for many years, only to relapse years or even decades later from metastatic disease originating from their original cancer. Extensive research has shown how cancer cells, often as solitary cells or very small clumps, can remain dormant at metastatic sites for years or decades, but researchers lack a good understanding of the conditions that favor their reawakening.

Previous studies have revealed that inflammation can promote dormant cancer cell awakening. During the COVID-19 pandemic, Aguirre-Ghiso initiated experiments using animal models of breast cancer, together with Mercedes Rincon, Shi Biao Chiao, and Bryan Johnson. They asked whether respiratory viral infections, such as the flu virus or SARS-CoV2, known to cause massive inflammation in the lungs, could trigger metastatic progression in the lungs.  

The results were striking, DeGregori says: “Infection of the animal models with either flu virus or SARS-CoV2 led to massive expansion — more than 100-fold — of the previously dormant breast cancer cells in the lungs.” Though only breast cancer was modeled in the mice, DeGregori says that the findings are likely applicable to other types of cancer. “Dormant cancer cells are like the embers left in an abandoned campfire, and respiratory viruses are like a strong wind that reignites the flames,” DeGregori says.

Dormant cancer cells are like the embers left in an abandoned campfire, and respiratory viruses are like a strong wind that reignites the flames

Significant effect

These results prompted the team to reach out to collaborators who could analyze human data to see if there were similar connections. Using patient data from UK and U.S. health databases, they looked at the effects of a COVID infection on previously diagnosed cancer patients. 

The team of epidemiological collaborators, led by Vermeulen, looked at people in the UK Biobank, a large population-based study in the United Kingdom, whose cancer was diagnosed either five or ten years ago. “This means they were almost certainly in remission,” Vermeulen says. “We studied those individuals who either got a positive or negative test for COVID-19 in 2020, the period before vaccination had started, and we asked, ‘Did they die from their cancer, and when?’ These analyses showed that the chance of dying from cancer was higher among the people that had contracted the virus. This risk seemed to be strongest in the year after contracting the virus.

"In the first two years, they were two times more likely to die of their cancer if they got COVID",  Vermeulen continues. “That’s a significant effect.” The magnitude of the increased risk in people mirrors the observed massive expansion of dormant cancer cells in the animal models.

Additional analyses of U.S.-based Flatiron Health data of women with a diagnosis of breast cancer, led by Junxiao Hu and Dexiang Gao, provided more specificity, showing that contracting COVID-19 significantly increased the risk of development of metastatic disease in the lungs. Again, results aligned with the experimental work in mice.

“Breast cancer cells stay in the lung, but they stay in very small numbers, in essentially a quiescent state,” DeGregori says. “What our data suggest is that if you are a cancer patient who has these dormant cells, you may end up living a normal life and dying with these dormant cells, without them ever awakening. But if you get a respiratory virus like influenza or COVID-19, the chance of those cells awakening is much greater — and with it your chance of dying from them.”

Vermeulen says it is important to note that the study examined the effect prior to the availability of COVID-19 vaccines. “At this time, it is not yet known whether vaccination has reduced this risk,” he says. “However, since vaccination results in a much milder dysregulation of the immune system, we speculate that the observed risk would be lower in vaccinated individuals. That said, further research is needed to determine whether any residual risk remains after vaccination."

The IL6 factor 

Driving the reawakening of dormant cancer cells, the researchers found, is interleukin 6 (IL6), a cytokine known to be involved in inflammatory responses. “It's interesting, because IL6 is actually targeted in some people who get COVID,” DeGregori says. “If you have severe COVID, they might give you an antibody that blocks signaling through the IL6 receptor to lessen the inflammatory response and increase survival."

Further investigation needed 

Given the significant results of their initial research, DeGregori and Rincon, along with the Aguirre-Ghiso lab at the Einstein College of Medicine in New York, now plan to look more closely at how the reawakening process works, how it can be prevented, and how the immune system might be engaged to eliminate awakened cancer cells.

They were recently awarded a 5-year grant from the National Cancer Institute to pursue these studies, although most of the results presented in the Nature publication relied on philanthropic support and intramural support of many of the institutions involved — including from the Cancer League of Colorado, a Patten Davis Endowed Chair in Lung Cancer Research to DeGregori, and the Kay Sutherland and Monika Weber Research Fund, and the Veterans Administration.

Vermeulen and his epidemiological colleagues are also extending their work to study important follow-up questions that arise from the current research. Does it matter which cancer you had before infection, or are all ex-cancer patients at risk? Is it only metastatic disease of the lung, or also other sites like the brain, liver and bone? Is there still a risk after vaccination for respiratory viruses like the flu or COVID?

To answer these questions, the researchers are now focusing specifically on Dutch data: they are combining information from the Netherlands Cancer Registry with COVID records and mortality data from Statistics Netherlands (CBS). The Dutch Cancer Society (KWF Kankerbestrijding) will fund the research, as these are urgent and socially relevant questions that need to be answered as soon as possible.

Questions and answers