Overcoming PD-1 Inhibitor Resistance with a Monoclonal Antibody to Secreted Frizzled-Related Protein 2 in Metastatic Osteosarcoma

Abstract

Secreted frizzled-related protein 2 (SFRP2) promotes the migration/invasion of metastatic osteosarcoma (OS) cells and tube formation by endothelial cells. However, its function on T-cells is unknown. We hypothesized that blocking SFRP2 with a humanized monoclonal antibody (hSFRP2 mAb) can restore immunity by reducing CD38 and PD-1 levels, ultimately overcoming resistance to PD-1 inhibitors. Treating two metastatic murine OS cell lines in vivo, RF420 and RF577, with hSFRP2 mAb alone led to a significant reduction in the number of lung metastases, compared to IgG1 control treatment. While PD-1 mAb alone had minimal effect, hSFRP2 mAb combination with PD-1 mAb had an additive antimetastatic effect. This effect was accompanied by lower SFRP2 levels in serum, lower CD38 levels in tumor-infiltrating lymphocytes and T-cells, and lower PD-1 levels in T-cells. In vitro data confirmed that SFRP2 promotes NFATc3, CD38 and PD-1 expression in T-cells, while hSFRP2 mAb treatment counteracts these effects and increases NAD+ levels. hSFRP2 mAb treatment further rescued the suppression of T-cell proliferation by tumor cells in a co-culture model. Finally, hSFRP2 mAb induced apoptosis in RF420 and RF577 OS cells but not in T-cells. Thus, hSFRP2 mAb therapy could potentially overcome PD-1 inhibitor resistance in metastatic osteosarcoma.

Immune Microenvironment in Osteosarcoma: Components, Therapeutic Strategies and Clinical Applications

“…Nasarre et al. ( 87 ) investigated the role of a monoclonal antibody targeting humanized secreted frizzled-related protein 2, a protein that promotes angiogenesis and metastasis, in metastatic osteosarcoma resistance to PD-1/PD-L1 inhibitors, and its impact on T cells. They found that humanized secreted frizzled-related protein 2 monoclonal antibody inhibited T cell proliferation and osteosarcoma metastasis by lowering the expression of NFATc3, CD38, and PD-1.…”

Immune checkpoint inhibitors in osteosarcoma: A hopeful and challenging future

“…Secreted frizzled-related protein 2 (SFRP2) promotes the migration of tumor cells and tube formation in endothelial cells, which are associated with OS metastasis. An in vitro study showed that a monoclonal antibody against SFRP2 combined with a PD-1 antibody synergistically inhibited the metastasis of OS ( Nasarre et al, 2021 ). Recruitment of MDSCs to the TME inhibits the effect of anti-PD1 therapy.…”

Recent and Ongoing Research into Metastatic Osteosarcoma Treatments

“…Very few studies have been published in which the authors detected established metastases in the lungs of mice by microscopy (in pilot experiments) and/or in vivo imaging before beginning treatment. Nasarre et al observed additive cooperation between PD-1 inhibitor and an antibody targeting Secreted Frizzled-Related Protein 2 (SFRP2) to reduce the number of metastases on the surface of mouse lungs by commencing treatment mice with the antibody in conjunction with a PD-1 inhibitor eight to twelve days after cells were intravenously injected [ 164 ]. The proteasome inhibitor ixazomib inhibited the growth of established pulmonary metastases after their presence was confirmed by bioluminescence imaging in two xenograft models, and moderately enhanced survival [ 165 ].…”