PD-1 blockade counteracts post–COVID-19 immune abnormalities and stimulates the anti–SARS-CoV-2 immune response

Abstract

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19–related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1 + T cells, as compared with healthy controls. Plasma levels of IL-1 β , IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1 -targeting miR–15-5p, in CD8 + T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post–COVID-19 immune abnormalities; indeed, we also noted an increased T cell–mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post–COVID-19 immune abnormalities and stimulates an anti–SARS-CoV-2 immune response.

Should we expect a wave of type 1 diabetes following SARS‐CoV‐2 pandemic?

“…Those alterations are similar and partially overlapped to those observed in other hyper inflammatory conditions such as cytokine release syndrome due to graft‐versus‐host disease or during chimaeric antigen receptor T cell therapies, acute respiratory distress syndrome and haemophagocytic lymphohistiocytosis induced by respiratory viruses 7 . A recent study showed as alteration in cytokine profile that persist also after resolution of the acute phase of COVID‐19 and resemble a sort of immune weakness 1 . These alterations can be reverted by PD‐1 blockade that is of interest for the onset and cure of autoimmune diabetes 1 .…”

“…Health efforts were initially aimed at containing the victims and the spread of the infection but now 2 years later, as cases continue to grow, the need to understand the long‐term sequelae of the infection is underway. More and more evidences showed that SARS‐Cov‐2 has tropism for various tissue and organs and that long‐lasting effects of COVID‐19 exist 1,2 . Recently, it has been described that glucose homoeostasis may be impaired during acute COVID‐19 and long after the recovery, with an increased insulin resistance and β ‐cell damage which may last up to 6 months 2 .…”

Clinical, radiological and pathological findings in patients with persistent lung disease following SARS-CoV-2 infection

“…Our results confirm that a multidisciplinary evaluation of these patients is needed (instead of a limited imagine evaluation) to identify key patient subgroups and their current optimal management. In particular, immune-histochemical evaluation of lung tissue may help revealing peculiar morphological and morpho-phenotypical changes of this new “Post-COVID/Long-COVID syndrome”, but also help in better understanding of pathogenic mechanisms and lay the groundwork to efficiently conducting therapeutic intervention studies and designing future follow-up plans as previously described [ 17 , 45 – 48 ]. Although the pathogenic role of different cell types and the mechanisms leading to different disease endotypes are not fully understood, this heterogeneity is likely to reflect different COVID-induced phenotypes of interstitial lung disease, probably in predisposed subjects to abnormal wound healing.…”

Inhibitory Immune Checkpoint Receptors and Ligands as Prognostic Biomarkers in COVID-19 Patients

“…Additionally, Yatim et al demonstrated that ICI therapy was not associated with severe COVID-19, rather it increases specific anti–SARS-CoV-2 T-cell immunity ( 152 ). Furthermore, another study found that the PD-1 inhibitor is able to enhance the specific T-cell immune response to SARS-CoV-2 antigens ( 153 ). In addition, TGF-β and IL-6 were upregulated in COVID-19 patients, suggesting that targeting these cytokines may improve COVID-19 outcomes ( 154 – 156 ).…”