Solid organ transplant (SOT) recipients receive therapeutic immunosuppression that compromises their immune response to infections and vaccines. For this reason, SOT patients have a high risk of developing severe coronavirus disease 2019 (COVID-19) and an increased risk of death from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Moreover, the efficiency of immunotherapies and vaccines is reduced due to the constant immunosuppression in this patient group. Here, we propose adoptive transfer of SARS-CoV-2-specific T cells made resistant to a common immunosuppressant, tacrolimus, for optimized performance in the immunosuppressed patient. Using a ribonucleoprotein approach of CRISPR-Cas9 technology, we have generated tacrolimus-resistant SARS-CoV-2-specific T cell products from convalescent donors and demonstrate their specificity and function through characterizations at the single-cell level, including flow cytometry, single-cell RNA (scRNA) Cellular Indexing of Transcriptomes and Epitopes (CITE), and T cell receptor (TCR) sequencing analyses. Based on the promising results, we aim for clinical validation of this approach in transplant recipients. Additionally, we propose a combinatory approach with tacrolimus, to prevent an overshooting immune response manifested as bystander T cell activation in the setting of severe COVID-19 immunopathology, and tacrolimus-resistant SARS-CoV-2-specific T cell products, allowing for efficient clearance of viral infection. Our strategy has the potential to prevent severe COVID-19 courses in SOT or autoimmunity settings and to prevent immunopathology while providing viral clearance in severe non-transplant COVID-19 cases.
【저자키워드】 COVID-19, SARS-COV-2 infection, CRISPR-Cas9, T cell therapy, adoptive immunotherapy, Solid organ transplant recipients, COVID-19 immunopathology, 【초록키워드】 SARS-CoV-2, Autoimmunity, viral infection, Vaccine, immune response, severe COVID-19, Vaccines, Immunotherapy, Sequencing, Infection, Immunosuppression, immunopathology, viral clearance, flow cytometry, RNA, specificity, T cell, therapeutic, Patient, death, convalescent, TCR, T cell receptor, single-cell, T cell activation, Donor, Coronavirus-2, COVID-19 cases, Immunosuppressed, Efficiency, solid organ, ribonucleoprotein, SOT, high risk, bystander, acute respiratory syndrome, increased risk, recipients, severe coronavirus disease, transfer, recipient, single-cell level, approach, Prevent, Course, reduced, manifested, analyses, receive, efficient clearance, SARS-CoV-2-specific T cell, SOT patient, 【제목키워드】 severe COVID-19, T cell, treat, Prevent, immunosuppressed patient,