OAB-020: The role of checkpoint inhibitor PD-1H/VISTA in Multiple Myeloma bone disease

Abstract

<h3>Background</h3> Multiple myeloma (MM) bone disease remains one of the most devastating complications of this incurable cancer, causing bone fractures, pain, mobility issues, and neurological deficits. MM cells secret pro-osteoclastogenic factors which lead to osteoclast (OCL) activation. Our previous work showed that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor highly secreted by MM cells and induces OCL fusion and bone resorption independently of its proteolytic activity (JCI 2016). We recently reported that MMP-13 binds to checkpoint inhibitor programmed death-1 homolog (PD-1H/VISTA), a surface receptor that is expressed on OCLs and mediates MMP-13 induced OCL fusion and bone resorption activity (ASH 2019). Bone resorption activity is significantly impaired in Pd-1h-/- OCLs in vitro. However, the function of PD-1H in MM bone disease has not been defined. <h3>Methods</h3> The role of PD-1H in MM bone disease was investigated using the intratibial 5TGM1 Rag2-/- MM bone disease mice model. Pd-1h-/-Rag2-/- mice were generated by crossbreeding Pd-1h-/- with Rag2-/- mice. Firefly luciferase-expressing 5TGM1 cells were intratibially injected into age and sex-paired Rag2-/- or Pd-1h-/-Rag2-/- mice (N=10). 3 weeks later, tibiae were harvested for quantitative micro-CT followed by histological analysis. <h3>Results</h3> Morphological analyses of trabecular and cortical bones confirmed that Pd-1h-/- recipient mice exhibited significantly less 5TGM1-induced bone loss (P<0.05). In trabecular bone, 5TGM1 induced 40.0% decrease of bone volume fraction in Rag2-/- mice vs 12.5% in Pd-1h-/-Rag2-/- mice, 7.3% decrease of trabecular bone numbers in Rag2-/- mice vs 0.6% in Pd-1h-/-Rag2-/- mice, 12.1% decrease of trabecular bone thickness in Rag2-/- mice vs 4.2% in Pd-1h-/-Rag2-/- mice, 8.1% increase of trabecular bone spacing in Rag2-/- mice vs 0.6% in Pd-1h-/-Rag2-/- mice, and 22.2% increase of specific bone surface in Rag2-/- mice vs 5.5% in Pd-1h-/-Rag2-/-mice. Similar effects were observed in cortical bone. 5TGM1 induced 18.9% decrease of cortical bone thickness in Rag2-/- mice vs 1.6% in Pd-1h-/-Rag2-/- mice, 7.28% decrease of cortical bone area fraction in Rag2-/- mice vs 2.7% in Pd-1h-/-Rag2-/- mice, and 8.19% decrease of cortical tissue mineral density in Rag2-/- mice vs 1.7% in Pd-1h-/-Rag2-/- mice. <h3>Conclusions</h3> Taken together, our study, for the first time, reveals that checkpoint inhibitor PD-1H/VISTA is the critical receptor for MMP-13 in osteoclasts, thereby mediating MMP-13-induced osteoclast fusion, activation, and bone resorption. MM-induced trabecular bone loss was significantly lower in Pd-1h-/- mice, demonstrating that PD-1H/VISTA plays a critical role in MMP-13-induced MM bone disease. Given the checkpoint role of PD-1H/VISTA in cancer immunosuppression, we further posit that targeting the interaction of MMP-13 and PD-1H may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment.