When the coronavirus was declared a pandemic last year, oncologists questioned whether cancer patients would be disproportionately impacted by the virus. As poor COVID-19 outcomes were recorded across this community, researchers set out to explore if certain biological underpinnings were the cause. Recently, a study published in Scientific Reports, determined that a number of proteases might affect the severity of COVID-19 symptoms, determined by RNA expression of key molecules involved in the infectious process (2021; https://doi.org/10.1038/s41598-021-84731-7).
This research analyzed a cohort of 38,628 cancer patients to determine factors causing the worsened COVID-19 responses. The large database of tumors was profiled by whole-transcriptome sequencing, from which researchers hypothesized that ACE2 and protease gene expression would vary across tumor types. High expression was presumed to be associated with an increased risk of infection and severe course of the disease.
The subsequent data from this study found that ACE2, TMPRSS2, and other proteases were key factors necessary for viral attachment to and entry into target cells. Further, infiltration with T-cell and natural killer (NK) cell infiltration were particularly pronounced in ACE2-high tumors. Data also found substantial variability of expression of ACE2 and TMPRSS2 across tumor types while identifying subpopulations expressing ACE2 at very high levels. According to researchers, in the case of some tumor types, especially in gastrointestinal cancers, the expression of ACE2 and TMPRSS2 is highly correlated.
Another key takeaway from this investigatory research was that there were significant differences in ACE2 and protease expression in normal and malignant tissues within a subgroup of patients expressing very high levels of ACE2 RNA. According to the research, the increased presence of inflammatory cells in tumors displaying high ACE2 levels may contribute to the complex pathophysiologic picture of COVID-19 as well.
While this study offers great insight into the negative COVID-19 outcomes seen in cancer patients, it is only the first systematic assessment of RNA expression of key molecules involved in the infectious process. The suggestion that subsets of patients with specific gene expression profiles may be associated with heightened susceptibility to SARS-CoV-2 infection is an important takeaway, although additional research is needed for concrete conclusions to be made.
"We were all hungry and desperate for any scientific information that might help us uncover individual vulnerability and, specifically, the vulnerability in cancer patients," noted John Marshall, MD, Chief of the Division of Hematology and Oncology at Georgetown University. "There was some suggestion that in, say, lung cancer patients [and] some of the hematologic malignancies, there was an increased vulnerability. We felt that we needed to figure out if we could predict or develop some sort of scientific prospective analysis that might enable us to stratify patients according to their risk so that we could encourage patients to continue in-person care."
If RNA expression and poor COVID-19 outcomes are correlated in cancer patients as suspected, researchers believe malignant tumors may function as viral reservoirs and possibly promote their frequently detrimental hyperimmune response. Using this biological explanation as a foundation for why cancer patients do poorly when afflicted with COVID-19, researchers can continue to assess patient data to make long-term conclusions.
Marshall affirmed that, right now, these results are not something an oncologist will incorporate into a routine test. He explained that, if somebody came into the hospital with a COVID-19 infection, they would need to send off a test to determine ACE2 levels.
In terms of COVID-19, he noted that what researchers don't yet have with this subgroup is crossing the data with patients who, in fact, were infected with COVID-19. Therefore, this was more of an observational study for patients to set the stage for this. Marshall noted that what should be done subsequently is to look at those cancer patients who were infected with COVID-19 and measure their levels to see if they are correlated with outcomes.
"I think what we're really looking for here is longer-term outcomes to predict the severity of infection and, possibly, mechanisms to interfere and treat the virus," Marshall said. "I think it is initially an observational study, an important observational study at a time of pandemic. Any scientific data to help us understand the COVID-19 illness is valuable."
Lindsey Nolen is a contributing writer.
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