Respiratory Viruses Wake Up Dormant Cancer Cells

Cancer remission, in which tumor cells enter a dormant state and a patient’s symptoms subside, can persist for years or decades.¹ Both the cancer cells themselves and the tumor microenvironment maintain this period of inactivity.² While inflammation has been shown to disrupt this microenvironment, leading to metastasis, the mechanisms of this process remain unclear.

Seeing a trend in increased cancer deaths in the first two years of the COVID-19 pandemic, cancer biologists Julio Aguirre-Ghiso at the Albert Einstein College of Medicine and James DeGregori at the University of Colorado suspected that viral infections could be activating dormant cancer cells. In partnership with researchers at Utrecht University, the teams showed that inflammation from viral infections activated dormant cancer cells and increased metastasis.³ The findings, published in Nature, provide important insights into cancer remission for clinicians.

“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 said in a press release about the study findings.

Using two models of breast cancer with dormant cells, the researchers infected mice with either influenza A or mouse-adapted SARS-CoV-2. They saw that the number of metastatic cells increased between three and 15 days after infection and remained high over nine months. This awakening coincided with changes to cell surface markers and gene expression, with previously dormant cells expressing epithelial markers and genes related to angiogenesis and crosslinking collagen. These are characteristics of active cancer cells.

To mechanistically explore how the infection response activated dormant cancer cells, the researchers focused on the inflammatory cytokine interleukin 6 (IL-6), which is expressed early during viral infection. In contrast to wildtype mice, the researchers saw decreased cancer cell activation and metastasis in mice deficient for IL-6.

Since IL-6 levels fall after the initial phase of the infection, the team studied other immune factors that could maintain the cancer cells’ activation. They showed that depleting CD4⁺ T cells decreased the numbers of activated dormant cells later after infection and increased the amount of cytotoxic CD8⁺ T cells in the lungs. Suspecting that the CD4⁺ T cells could be restricting these cytotoxic cells from entering the tissue, the researchers found that the reawakened cancer cells reprogrammed incoming CD4⁺ T cells toward antitumor activity, including restricting CD8⁺ T cells.

Finally, the researchers studied the correlation between cancer deaths and COVID-19 infections using two different datasets. In both cases, they saw an associated increased risk of deaths in the months following a documented infection with COVID-19.

“Our findings indicate that individuals with a history of cancer may benefit from taking precautions against respiratory viruses, such as vaccination when available, and discussing any concerns with their healthcare providers,” Aguirre-Ghiso said in the press release.