BioModels

Introduction

Tumor immune interaction has become a key area of research due to promising success in cancer immunotherapy. Immunosuppression is one of the key mechanism through which cancer escapes immune targeting and this process involves a complex interplay between cancer and immune cells. One of the significant players, PD-L1, produced and presented by cancer cells, plays a vital role in the suppression of T-cell function, crucial for immune surveillance (Figure1a). Thus, targeting PD-L1 and its downstream signaling has a clinical significance in cancer immunotherapy [1, 2] and multiple drugs targeting PD-L1 have been approved recently by FDA for different cancers (e.g. Avelumab for metastatic merkel cell carcinoma; Atezolizumab for locally advanced or metastatic urothelial carcinoma) [3, 4, 5]. Thus, this complex interaction between immune cells and cancer cells makes them an interesting system to investigate using quantitative models. Mathematical models aid in the study of drug dosing & response prediction, biomarker identification and test-able hypothesis generation for biological mechanisms. The Theinmozhi et al. 2018 [7] model provides mechanistic insight into the PD1 receptor (receptor for PD-L1) mediated inhibition of TCR signaling in T cells and role of Lck in this process.

Model

The model includes different TCR signaling molecules like CD3, CD28, ZAP70, SLC76. It mainly contains the early TCR signaling involving binding of ZAP70, LATs, GADs to activate SLP76 and direct binding of PI3K with CD38 resulting in PI3K activation. The model also covers the different activation and inactivation states of Lck regulated by PD1 (Figure 1b). PD1 recruits SHP2, a phosphatase, to dephosphorylate and inhibit Lck and TCR signaling pathway. The authors used this model to investigate the role of Lck in PD1 mediated inhibition of TCR signaling.

Figure1: a. Basic Tumor T cell interaction involving PD-L1 and PD1 (figure taken from Sznol et al, 2013 [6]) b. Network diagram of the model with the major interactions and signaling assembly (figure taken from Arulraj T, 2018 [7]).

Result

Model simulation for different time courses, at varied species/parameter concentrations aligned well with the reported literature [7]. The model predicted the recruitment and activation of various components of TCR signaling in the absence and presence of PD1(100 to 500 nM) stimulation . In the absence of PD1 stimulation, TCR signaling promoted the recruitment and activation of PI3K and ZAP70. In the presence of PD1 (100 and 300nM), TCR signaling is inhibited resulting in release of PI3K and ZAP70 from the receptor (represented as % of free protein) (Figure 2 a,b,c). Also, the inhibitory activity of PD1 on Lck can be observed in Figure 2d, where PD1 (300nM) activation decreases the active form of Lck (by ~20%) by dephosphorylating activatory phosphorylation.