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Published on: February 8, 2018
Altered ACE2 and interferon landscape in the COVID-19 microenvironment correlate with the anti-PD-1 response in solid
Karthikeyan Subbarayan1, Ahmed Al-Samadi2,3, Helene Schäfer1
1Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112, Halle (Saale), Germany.
Abstract:
Angiotensensin-converting enzyme-2 (ACE2) is a receptor for SARS-CoV-2, allowing the virus to enter cells. Although tumor patients infected by SARS-CoV-2 often have a worse outcome, the expression, function and clinical relevance of ACE2 in tumors has not yet been thoroughly analyzed. In this study, RNA sequencing (RNA-seq) data from tumors, adjacent tissues and whole blood samples of COVID-19 patients from genome databases and from tumor cell lines and endothelial cells infected with different SARS-CoV-2 variants or transfected with an ACE2 expression vector (ACE2high) or mock (ACE2low) were analyzed for the expression of ACE2 and immune response relevant molecules in silico or by qPCR, flow cytometry, Western blot and/or RNA-seq. The differential expression profiles in ACE2high vs. ACE2low cells correlated with available SARS-CoV-2 RNA-seq datasets. ACE2high cells demonstrated upregulated mRNA and/or protein levels of HLA class I, programmed death ligand 1 (PD-L1), components of the antigen processing machinery (APM) and the interferon (IFN) signaling pathway compared to ACE2low cells. Co-cultures of ACE2high cells with peripheral blood mononuclear cells increased immune cell migration and infiltration towards ACE2high cells, apoptosis of ACE2high cells, release of innate immunity-related cytokines and altered NK cell-mediated cytotoxicity. Thus, ACE2 expression was associated in different model systems and upon SARS-CoV-2 infection with an altered host immunogenicity, which might influence the efficacy of immune checkpoint inhibitors. These results provide novel insights into the (patho)physiological role of ACE2 on immune response-relevant mechanisms and suggest an alternative strategy to reduce COVID-19 severity in infected tumor patients targeting the ACE2-induced IFN-PD-L1 axis.
Insights
Angiotensin-converting enzyme-2 (ACE2) expression in tumors influences immune responses and host immunogenicity. Targeting the ACE2-induced interferon-programmed death ligand 1 (IFN-PD-L1) axis may reduce COVID-19 severity in cancer patients.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- Angiotensin-converting enzyme-2 (ACE2) is the cellular receptor for SARS-CoV-2.
- The role and clinical relevance of ACE2 in tumors, particularly in COVID-19 patients, remain under-investigated.
- Tumor patients infected with SARS-CoV-2 often experience poorer outcomes.
Purpose of the Study:
- To analyze the expression, function, and clinical relevance of ACE2 in tumors.
- To investigate the impact of ACE2 expression on immune response-related molecules and mechanisms.
- To explore potential therapeutic strategies targeting the ACE2 pathway in cancer patients with COVID-19.
Main Methods:
- Analysis of RNA sequencing data from tumor and adjacent tissues, and whole blood of COVID-19 patients.
- In silico and experimental analysis (qPCR, flow cytometry, Western blot, RNA-seq) of ACE2 and immune molecules in tumor cell lines and endothelial cells with varying ACE2 expression levels.
- Co-culture experiments with ACE2-expressing cells and peripheral blood mononuclear cells.
Main Results:
- ACE2-high cells showed upregulated mRNA and/or protein levels of HLA class I, programmed death ligand 1 (PD-L1), antigen processing machinery (APM) components, and interferon (IFN) signaling pathway.
- Co-culture with ACE2-high cells increased immune cell migration, infiltration, apoptosis, innate immune cytokine release, and altered NK cell-mediated cytotoxicity.
- ACE2 expression correlated with altered host immunogenicity in various model systems and upon SARS-CoV-2 infection.
Conclusions:
- ACE2 expression significantly influences tumor immunogenicity and immune cell interactions.
- The ACE2-induced IFN-PD-L1 axis represents a potential therapeutic target to mitigate COVID-19 severity in cancer patients.
- Findings provide novel insights into ACE2's role in immune response and suggest strategies for managing SARS-CoV-2 infection in tumor patients.
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