Keeping exhausted T-cells in check in COVID-19

ABSTRACT

Background: Clinical data suggest an aggravated COVID-19 disease course in cancer patients treated with immune checkpoint inhibitors (ICI). European guidelines advise to defer ICI therapy until complete resolution of COVID-19. However, mechanistic insight into how ICI impacts COVID-19 immunopathology is absent. Methods: We performed single-cell RNA- and T-Cell Receptor-sequencing (TCR-seq) on bronchoalveolar lavage fluid of COVID-19 pneumonia (n=19) and non-COVID pneumonia (n=10), and co-analyzed CD8+ T-cells with publicly available tumor-infiltrating T-cell data of treatment-naïve and ICI-treated patients (Sade-Feldman, Cell, 2018;Lambrechts, Nat Med, 2018). Cell lineages were determined by trajectory inference (Slingshot, Monocle v2) and stratified per condition. Pathogen- or tumor-directed T-cells were defined based on clonal selection (Zhang, Nature, 2018). To identify ICI responsive cells, we calculated a score derived from a validated gene set denoting ICI reactivity (Okamura, J. Autoimmun, 2019). Results: We identified 3 CD8+ T-cell lineages, with ‘Naïve’ T-cells transitioning into ‘Effector Memory’ cells and then branching into either ‘Recently Activated Effector Memory (TEMRA)’, ‘Exhausted (TEX)’ or ‘Resident Memory (TRM)’ T-cells. In COVID-19, clonal expansion indicating a SARS-CoV-2 antigen-specific T-cell response, was mainly observed in the highly cytotoxic ‘TEMRA’ lineage. In contrast, tumor-specific T-cells were found in the ‘TEX’ lineage. Of importance, the ICI responsiveness score was significantly higher in the non-pathogen-directed ‘TRM’ and ‘TEX’ cells in COVID-19. In cancer, ‘TEX’ cells were shown to be ICI responsive as expected. [Formula presented] Conclusions: We are the first to provide a mechanistic rationale for an aggravated COVID-19 disease course in ICI-treated patients. Whereas ICI reactivates tumor-directed ‘exhausted’ T-cells in cancer, it preferentially potentiates non-pathogen-directed T-cells in COVID-19, thereby contributing to lung damage without boosting the antiviral immune response. Clinical trial identification In-depth Immunological Investigation of COVID-19 (COntAGIouS). - Clinical Trial identifier NCT04327570. - Ethical approval obtained by the Ethics Committee of University Hospitals - KU Leuven. File number S63881. Legal entity responsible for the study University Hospitals - KU Leuven. Funding: Kom op tegen Kanker (Stand up to Cancer). Disclosure All authors have declared no conflicts of interest.