Immune check-point inhibitors in Idiopathic Pulmonary Fibrosis (IPF)

Immune checkpoint molecules are widely known for their role in cancer, where they help malignant cells escape immune-mediated removal. Their discovery was a turning point in cancer therapy, and led to the development of immune checkpoint inhibitors which are now widely and successfully used in cancer immune therapy (1).

These molecules are not uniquely expressed in cancer cells. They just exploit a previously existing mechanism to their advantage. So what role do these checkpoint molecules play in normal, healthy cells? The immune system has built-in ways of distinguishing self from non-self, a process critical to our defense in front of infectious agents (bacteria and viruses). In addition, it also has inherent internal quality control mechanisms that ensure the removal of aged and/or damaged "self" cells. PD-L1 is one of the molecules involved in this complex process (2), and in this paper, we analyze its expression in non-cancerous lung epithelial cells. Previous papers described its increased expression in the mesenchymal compartment of IPF patients (3). We identify its expression on a small population of epithelial cells and we show that this population is increased in IPF. 

What are the therapeutic implications of this discovery? IPF has two crucial features: chronic epithelial damage, and myofibroblasts (a sub-type of a mesenchymal cell) accumulation, many of which express PD-L1.  Thus, PD-L1 checkpoint therapy was proposed as a potential therapy to prevent or even revert this accumulation. However, PD-L1 is also involved in conferring protection to epithelial progenitors, which are crucial for maintaining and regenerating a functional lung epithelium. It remains to be determined experimentally what would be the consequences of eliminating this protection mechanism by blocking PD-L1 in normal or IPF lungs. However, it has been shown clinically that PD-L1 blockade, although beneficial as anti-tumor therapy, has detrimental side effects in the lung (4). Future studies will determine precisely the target population, and the mechanisms underlying this toxicity. 

1. Sznol, M.; Chen, L. Antagonist Antibodies to PD-1 and B7-H1 (PD-L1) in the Treatment of Advanced Human Cancer. Clin. Cancer Res. 2013, 19, 1021–1034, doi:10.1158/1078-0432.CCR-12-2063

2. Sharpe, A.H.; Wherry, E.J.; Ahmed, R.; Freeman, G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 2007, 8, 239–245, doi:10.1038/NI1443.

3. Geng, Y.; Liu, X.; Liang, J.; Habiel, D.M.; Kulur, V.; Coelho, A.L.; Deng, N.; Xie, T.; Wang, Y.; Liu, N.; et al. PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis. JCI insight 2019, 4, doi:10.1172/JCI.INSIGHT.125326.

4. Martins, F.; Sofiya, L.; Sykiotis, G.P.; Lamine, F.; Maillard, M.; Fraga, M.; Shabafrouz, K.; Ribi, C.; Cairoli, A.; Guex-Crosier, Y.; et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 2019, 16, 563–580, doi:10.1038/S41571-019-0218-0.



Roxana Wasnick MD PhD 

Medical Scientist

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