Altered ACE2 and interferon landscape in the COVID-19 microenvironment correlate with the anti-PD-1 response in solid tumors.

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 (ACE2 ^high ) or mock (ACE2 ^low ) 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 ACE2 ^high vs. ACE2 ^low cells correlated with available SARS-CoV-2 RNA-seq datasets. ACE2 ^high 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 ACE2 ^low cells. Co-cultures of ACE2 ^high cells with peripheral blood mononuclear cells increased immune cell migration and infiltration towards ACE2 ^high cells, apoptosis of ACE2 ^high 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.
Competing Interests: Declarations. Ethical approval: Ethical approval for this study was obtained from the Finnish Red Cross and the MLU for the usage of PBMNC in this study. All other datasets used in this work are obtained from public databases and are freely available. This work did not include any experiments on humans or animals. The patients involved in the public databases have been enrolled after ethical approval and deemed exempt for ethical approval. Consent to participate: Not applicable. Consent for publication: All authors read the final version of the manuscript and gave consent for publication. Competing interests: There are no competing interests. The authors have no relevant financial or non-financial interests to disclose.
(© 2024. The Author(s).)