Anti-IFNG monoclonal antibody, clone YNH2.3 [Brilliant Violet 785]

Transplacental viral and parasitic infections have been shown to initiate an innate response in the mammalian embryo by increasing the expression of pro-inflammatory cytokines such as interferon-gamma (Ifng). However, the developmental consequences of an activated innate immunity and, in particular, the effects of induction of Ifng expression independent of infection have been largely overlooked. Here, we demonstrate in vivo that the conditional overexpression of Ifng in metanephric mesenchymal (MM) progenitors results in renal agenesis or hypoplasia. Cell death was observed in and around the MM region of E10.5-11.5 mutants where Ifng was constitutively expressed during early kidney development and resulted in a retardation of branching morphogenesis. Furthermore, isolated mutant or normal Ifng-treated metanephroi replicated this phenotype in culture, demonstrating the inherent nature of the aberrant morphogenesis. The expression of renal progenitor marker Sall 1 was significantly decreased in the MM of mutant kidneys, suggesting that a reduction in Sal may be the cause of cell death in the MM during early kidney development and that, in turn, retards UB branching in the mutants. Therefore, the aberrant induction of Ifng expression, as part of an innate immune response, may contribute to renal agenesis or hypoplasia during early metanephric development by regulating the MM progenitor population.

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA111(43):15544-15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.