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669 Computational analysis of mutual feedback regulations between IDO1 and PD-L1
  1. Jian Zhu1 and
  2. Rebecca Zhu2
  1. 1OmicsHealth LLC, Bethesda, MD, USA
  2. 2Winston Churchhill High School, Potomac, MD, USA


Background PD-L1 is a validated biomarker for anti-PD-1/PD-L1 therapies and its expression can be regulated by IDO1, and vice verse IDO1 can regulate PD-L1 expression indirectly through various signaling pathways. Concurrent inhibition of IDO1 and PD-1/PD-L1 may have enhanced anti-tumor effects.

Methods In this study, computational models were established to identify factors involved in interactions between these two therapeutic targets. Abstracts published on IDO1, PD-1, PD-L1, anti-PD1/PD-L1 were downloaded from PubMed, and analyzed by natural language processing and text mining. The information on interactions among gene, compound/therapy, cell/animal model, pathway and disease was extracted. Two gene networks, IDO1->PD-L1 and PD-L1->IDO1, were constructed (figures 1 and 2, respectively).

Results The PD-L1/IDO1 network is primarily mediated through IFN-gamma and Tregs. PD-L1 inhibits IFN-gamma production through down-regulation of NK cells, IL-2 and CD40 and activation of PD-1. In turn, diminished production of IFN-gamma inactivates AhR, IRF1, STAT1, COX2, NF-kappaB and M1 macrophages, leading to down-regulation of IDO1. On the other hand, PD-L1 could induce IDO1 expression through up-regulation of Tregs and PI3K/AKT pathway (figure 1). The key factors involved in the IDO1/PD-L1 network comprise MYC, EMT and IFN-gamma. MYC and EMT contribute to the positive feedback from IDO1 to PD-L1. IDO1 up-regulates IL-6, iNOS and beta-catenin, leading to activation of MYC and subsequent induction of PD-L1. IDO1 could also up-regulate PD-L1 through activation of MDSC, AhR, JAK/STAT, HIF1-alpha and NF-kappaB. However, IDO1 down-regulates IFN-gamma, which is a leading factor inducing PD-L1 expression (figure 2).

Abstract 669 Figure 1

The PD-L1/IDO1 networkOrgan curve with an arrow indicates a positive interaction between nodes. Green curve with a bar indicates a negative interaction between nodes

Abstract 669 Figure 2

The IDO1/PD-L1 networkOrgan curve with an arrow indicates a positive interaction between nodes. Green curve with a bar indicates a negative interaction between nodes

Conclusions As the network analyses revealed, IDO1 and PD-L1 are involved in complex mutual feedback regulations. Inhibition of IDO1 could either up- or down-regulate PD-L1, and enhance or reduce efficacy of anti-PD-1/PD-L1. The factors involved in the mutual feedback regulations could serve as biomarkers to determine and monitor the efficacy of combining IDO1 and PD-1/PD-L1 inhibitors, as well as additional therapeutic targets. The literature-based modeling approach facilitates the development of combination strategies especially when the experimental evident is lacking.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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