RESUMEN
Since their discovery immune checkpoint inhibitors (ICI) have dramatically changed the treatment landscape for many cancers. In addition to their efficacy they are generally well tolerated, however, they have led to a new range of immune-related adverse events (irAEs) including pneumonitis. While not the most frequently reported immune-related adverse event in the clinical trial setting, recent real-world data suggests a significantly higher rate of pneumonitis leading to treatment suspension or cessation. It also appears to disproportionately contribute to immune-related mortality, particularly with anti-PD-1/PD-L1 treatment. While indicators have emerged regarding risk factors, incomplete prospective recording of patient characteristics hampers strong conclusions. Presenting symptoms are non-specific and the differential diagnosis is broad, made more complex by concomitant treatment with traditional chemotherapy or radiotherapy. Radiological findings are diverse and inconsistent terminology makes comparison and more complete characterization difficult. Further, little is known about the role of baseline testing or surveillance for early detection of pneumonitis, or the real-world role of bronchoscopy or biopsy in assessment. Scant literature exists to direct these complex decisions, so treatment guidelines have been published based on expert consensus. Here we provide a narrative review of what is known about ICI pneumonitis and propose key questions to enhance our understanding into the future.
RESUMEN
RNA-specific adenosine deaminase (ADAR)-mediated adenosine-to-inosine (A-to-I) editing is a critical arm of the antiviral response. However, mechanistic insights into how A-to-I RNA editing affects viral infection are lacking. We posited that inosine incorporation into RNA facilitates sensing of nonself RNA by innate immune sensors and accordingly investigated the impact of inosine-modified RNA on Toll-like receptor 7 and 8 (TLR7/8) sensing. Inosine incorporation into synthetic single-stranded RNA (ssRNA) potentiated tumor necrosis factor alpha (TNF-α) or alpha interferon (IFN-α) production in human peripheral blood mononuclear cells (PBMCs) in a sequence-dependent manner, indicative of TLR7/8 recruitment. The effect of inosine incorporation on TLR7/8 sensing was restricted to immunostimulatory ssRNAs and was not seen with inosine-containing short double-stranded RNAs or with a deoxy-inosine-modified ssRNA. Inosine-mediated increase of self-secondary structure of an ssRNA resulted in potentiated IFN-α production in human PBMCs through TLR7 recruitment, as established through the use of a TLR7 antagonist and Tlr7-deficient cells. There was a correlation between hyperediting of influenza A viral ssRNA and its ability to stimulate TNF-α, independent of 5'-triphosphate residues, and involving Adar-1. Furthermore, A-to-I editing of viral ssRNA directly enhanced mouse Tlr7 sensing, when present in proportions reproducing biologically relevant levels of RNA editing. Thus, we demonstrate for the first time that inosine incorporation into immunostimulatory ssRNA can potentiate TLR7/8 activation. Our results suggest a novel function of A-to-I RNA editing, which is to facilitate TLR7/8 sensing of phagocytosed viral RNA.
