Severe instances of COVID-19 and influenza possess the capacity to “reprogram” lung cells, thereby creating a fertile ground for the proliferation of malignant cells.
During a respiratory viral illness, the interplay between the invading pathogen and the host’s immune defense mechanisms can trigger tissue damage and inflammation that persist for years after the virus has been cleared. Intense inflammation might culminate in pneumonia or respiratory failure, alongside the development of scar tissue, also known as fibrosis.
“Previously, we established that an acute influenza infection could induce chronic inflammation and fibrosis,” stated Professor Jie Sun of the University of Virginia, the lead author of this new study.
Given that inflammation and fibrosis are recognized risk factors for the onset of lung cancer, Sun was prompted to investigate whether influenza infection itself contributes to the development of primary lung cancer. When the COVID-19 pandemic emerged, Sun broadened his investigation to examine the link between COVID-19 infection and subsequent lung cancer risk.
“The COVID-19 pandemic offered us a unique setting to explore this [infection’s relationship with lung cancer risk] because a vast number of individuals simultaneously succumbed to the same virus,” he noted.
The research team undertook a retrospective cohort analysis utilizing the Epic Cosmos database, identifying 75.9 million adults who experienced mild or moderate COVID-19, severe cases (requiring hospitalization), or who remained uninfected throughout 2020–2021.
According to cancer diagnosis data extending into 2022, patients who suffered severe COVID-19 demonstrated a modest increase in overall cancer incidence and a heightened risk specifically for lung cancer. Even after accounting for variables such as sex, age, and smoking status, severe COVID-19 correlated with a 1.24-fold increased likelihood of developing cancer.
However, a limitation inherent in this retrospective method is the possibility that some individuals hospitalized with COVID-19 may have harbored pre-existing pre-cancerous lesions, which could have contributed both to the severity of the infection and the subsequent cancer development.
Sun and his colleagues then employed animal models to probe the underlying mechanisms by which a preceding respiratory infection elevates the susceptibility to lung cancer.
Mice were inoculated with either SARS-CoV-2, the influenza virus, or a control substance. Three weeks post-infection, cancer cells were introduced into their lungs. The researchers then monitored tumor dimensions and overall survival. They confirmed that prior exposure to either SARS-CoV-2 or influenza significantly accelerated tumor growth and drastically reduced survival rates.
Subsequent experimentation revealed that preceding viral pneumonia also fosters cancer development, suggesting that viral encounters prime the lungs for both tumor initiation and progression.
Single-cell sequencing performed on lung tissue at both 6 and 12 weeks following tumor induction showed that the prior infection reprogrammed neutrophils and macrophages, driving them to exhibit stronger pro-tumorigenic characteristics. Moreover, CD8+ T cells within tumors exposed to the virus displayed enhanced signs of exhaustion.
This epigenetic reshaping of these immune cells, induced by the viral exposure, intensifies pro-tumor inflammatory responses when oncogenes trigger tumor genesis, thus establishing an environment conducive to malignant cell prosperity.
Once a tumor has formed, the reprogramming of these immune cells extends its influence to the tumor microenvironment, which then dictates the trajectory of cancer cell growth.
“Epithelial cells also underwent epigenetic reprogramming due to the prior severe infection, resulting in the secretion of more pro-tumor inflammatory cytokines upon tumor emergence/exposure, which contributed to the creation of a cancer-supportive milieu,” Sun elaborated.
The researchers report that vaccination not only prevents hospitalization following viral infection but may also mitigate the long-term ramifications of the illness.
“We found that severe infection preceding cancer development was necessary in our experimental animal models,” Sun stated. “In those mouse trials, prior vaccination successfully prevented severe disease, thereby dampening the infection’s pro-tumor effects.”
Since human vaccination also aids in averting severe infection by ‘training’ the immune system to respond more effectively to pathogens, it stands to reason that vaccination might likewise alleviate the pro-tumor consequences of viral infections. Nevertheless, Sun cautions that definitive human evidence is required to fully substantiate this hypothesis.
Given that tissue damage and inflammation stemming from viral infection can persist for years, these findings imply that the elevated risk of lung cancer may also linger for months or years following apparent recovery from the viral illness.
Considering the tens of millions globally affected by long-term COVID-19 symptoms, this research carries substantial implications for clinical care protocols and cancer screening strategies.
“We believe individuals at high risk generally—such as smokers—should receive heightened attention regarding early lung cancer screening after they have suffered a severe preceding infection,” Sun advised.
Furthermore, understanding how the reprogramming of immune and epithelial cells fuels cancer cell growth can spur additional investigation into biomarkers and therapeutic agents.
“There is an urgent need to identify molecular signatures or biomarkers that can better predict an individual’s lung cancer risk, alongside devising treatment modalities specifically targeting the pro-cancerous niches established by viruses for treating lung cancer,” Sun concluded.
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