Context matters

Summary

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Signaling and function of immune inhibitory receptors (IIRs) is tightly regulated and hence quite complex. Understanding IIR signaling and function is essential for future development of IIR based immunotherapy. In this thesis, we investigated different components of signaling and function of three different IIRs and gained new knowledge about IIR signaling and function. Firstly, we studied the signaling motif of CD200R in Chapter 2. Here, we identified novel conserved regions in the cytosolic tail of CD200R using phylogenetic analysis. Additionally, we showed that these regions are required for CD200R function. With that, we extended the CD200R intracellular signaling motif in mammals to the unique EEDExxPYxxYxxKxNxxY. Secondly, we investigated the role of inflammation on PD-1 blockade therapy in Chapter 3. Here, we showed that IFN-α reduces the effectiveness of PD-1 blockade in terms of IFN-γ secretion in vitro. Additionally, we assessed the type I IFN score in a cohort of 22 melanoma patients treated with PD-1 blockade therapeutic nivolumab. In this cohort, both type I IFN score in vivo and IFN-γ secretion in vitro in the presence of PD-1 blockade did not correlate with PD-1 blockade therapy response in melanoma patients. Finally, we explored the functional interaction between LAIR-1 and LILRB4, another IIR, in Chapter 4. Here, we confirmed that LAIR-1 and LILRB4 proteins interact in vitro and that LAIR-1 and LILRB4 interact on cells. Additionally, while we did not find evidence for LAIR-1 and LILRB4 to act as functional ligands for each other in trans, we showed that, when co-expressed, in cis LAIR-1:LILRB4 interaction hinders the inhibitory function of LILRB4.

Altogether, we investigated several aspects of how IIRs function, including how they transmit signals, the influence of inflammation, and how IIRs interact with each other. Based on our findings, we conclude that the context in which an IIR operates is crucial for its effect: context matters!