NEW YORK – A subset of tumors from several cancer types appear to express wildly variable levels of genes that SARS-CoV-2 exploits to enter human cells, according to recently published research in which investigators sought to understand why cancer patients with COVID-19 tend to have poor outcomes.
In Scientific Reports earlier this month, investigators from Caris Life Sciences, the University of California at San Francisco, Georgetown University Medical Center, and elsewhere published a paper in which they hypothesized that SARS-CoV-2 may be able to wrangle its way into some tumor cells more effectively than others. While this notion still needs to be confirmed by looking at samples and clinical data from cancer patients diagnosed with COVID-19, the research so far hints that some tumor cell and cancer types could act as SARS-CoV-2 viral reservoirs within cancer patients.
"These findings suggest that subsets of cancer patients exist with gene expression profiles that may be associated with heightened susceptibility to SARS-CoV-2 infection, in whom malignant tumors function as viral reservoir and possibility promote the frequently detrimental hyper-immune response in patients infected with this virus," researchers led by Michael Korn, chief medical officer at Caris Life Sciences and a professor of medicine at UCSF's hematology and oncology division, wrote.
It is increasingly clear that cancer patients infected with the COVID-19-causing coronavirus tend to do poorly and have significantly worse outcomes than COVID-19 patients without cancer and vice versa, Korn explained.
For the study, researchers tapped into tumor transcriptome data for more than 38,600 samples from advanced cancer patients and looked for clues to these outcomes. The patients received genomic testing at Caris, a precision oncology company that conducts comprehensive tumor profiling and uses an artificial intelligence platform to discover new insights into disease biology and treatment.
"We felt it's our obligation to look into our data: is there anything we can contribute to understand why these patients are doing so poorly?" Korn said. "And, of course, that's the first step to helping them in an optimized way."
In particular, Korn and his colleagues focused on several protease enzyme-coding genes, including ACE2 and TMPRSS2, which code for a SARS-CoV-2 receptor and a host protein that appears to modify the SARS-CoV-2 spike protein after the virus makes its way into the cell.
"[O]ur investigation demonstrates significant differences in ACE2 and protease expression in normal and malignant tissues with a subgroup of patients expressing very high levels of ACE2 RNA," the authors wrote. "These might contribute to the developing complex pathophysiologic picture of COVID-19 and help guide prophylactic measures in patients with solid malignancies."
For the study, the researchers relied on high-throughput RNA panel sequencing data for 38,628 tumor samples from advanced cancer patients who were profiled at Caris between 2019 and 2020. Most of the tumor samples on hand came from individuals with locally advanced, unresectable or metastatic disease, Korn said, adding that matched normal tissues from the same organs were profiled when possible.
Within the available transcriptomes, they saw enhanced ACE2 expression, on average, in tumor or matched normal samples from younger patients — those under 65 years old — and in samples from men.
The team also highlighted specific cancer types showing enhanced average ACE2 expression, including colorectal adenocarcinoma, kidney cancer, non-epithelial ovarian cancer, and small intestinal malignancies.
"Obviously, we don't have clinical data to go along in infected patients, but I think it is a reasonable hypothesis that this high receptor expression somehow allows the viruses potentially to get more easily into cancer cells and that might then lead to enhanced virus production," Korn said.
The investigators also found clusters of tumors with much higher or lower ACE2 expression than the average for that cancer type, particularly in non-small cell lung cancer (NSCLC), breast carcinoma, cholangiocarcinoma, and neuroendocrine tumor sets.
"My personal interpretation is that it's more about the extreme cases that you definitely don't see in [matched normal samples], where you have very, very high expression" of the SARS-CoV-2 receptor-coding gene, Korn suggested.
The investigators also saw variable expression for another SARS-CoV-2-related serine protease-coding gene, TMPRSS2. Levels of TMPRSS2 appeared to be enhanced in NSCLC patients' samples and in more than a dozen other cancer types, they reported, adding that levels of that gene tended to notch up alongside ACE2 expression in colorectal, gastric, and esophageal, and other cancer types.
Prior studies have documented particularly poor outcomes in COVID-19 patients with lung cancer or hematological malignancies, prompting the team to take a closer look at a subset of NSCLC tumors with high ACE2 and TMPRSS2 expression.
Within the NSCLC set, the investigators saw higher-than-usual ACE2 expression in samples with marked tumor infiltration by T cells, natural killer cells, B cells, and other immune cells from the tumor microenvironment.
"There is this association of high ACE2 expression with a much 'hotter' immune infiltrate," Korn explained, noting that immune over-reactions, including so-called "cytokine storms" have been linked to more dangerous courses of COVID-19 disease and relatively poor SARS-CoV-2 infection outcomes in general.
"The fact that high ACE2 expression might set up a tumor to become infected with the virus and its relationship to an already-stimulated immune system, makes you wonder: is this a situation where the immune system gets very quickly fired up once the virus arrives?" he added.
The authors emphasized the need for follow-up analyses on cancer patients who have actually been infected with SARS-CoV-2, and Korn said that there are almost certainly other factors that impact COVID-19 severity and outcomes in cancer patients. Past studies have pointed to the importance of cancer patients' age, for example, as well as the presence of other underlying health conditions.
"These viral infection processes are extremely complex and the interaction with the immune system is complex, so it's probably not a simple tumor cell-to-virus production relationship," he said. "It's probably very much more complex."
The team is hoping to tap into the network of cancer centers and research institutions within the Caris Precision Oncology Alliance to access cancer patients' samples and corresponding clinical information, Korn explained. "We are looking into possibilities to work with that group to find patients and ask those questions," he said. "It's not [a trivial undertaking], but I think it would be very important to follow up on it."
Members of the research team are also considering the possibility of prospectively following ACE2 expression in circulating tumor DNA and RNA from individuals with cancer, using an upcoming liquid biopsy technology from Caris.
"For us, this is a baseline assessment. We are really looking forward to performing additional analysis when our new blood assay comes out" in a few months that combines DNA and RNA analysis of circulating tumor nucleic acids from whole-exome sequencing, Korn noted. "That will be a fantastic tool to address some of these questions," he explained, "in terms of what happens in the tumor once the infection hits, what happens at different phases of the infection."