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STING Agonists as Cancer Therapeutics
Article

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

1
Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
2
Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
3
Department of Pediatrics, The Faris D. Virani Ewing Sarcoma Center at the Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
P.N. and D.I.G. contributed equally to the research and writing of this manuscript.
Academic Editor: David Wong
Cancers 2021, 13(11), 2696; https://doi.org/10.3390/cancers13112696
Received: 27 April 2021 / Revised: 25 May 2021 / Accepted: 27 May 2021 / Published: 30 May 2021
(This article belongs to the Section Pediatric Oncology)
Osteosarcoma (OS) is the most common bone tumor in the pediatric population, and long-term survival occurs in less than a third of the population with metastatic or recurrent tumors. Secreted frizzled-related protein 2 (SFRP2) promotes metastatic OS cell migration and tumor angiogenesis. This study aimed to assess the role of antagonizing SFRP2 with a humanized monoclonal antibody to SFRP2 (hSFRP2 mAb) in OS metastases in vivo and the role of SFRP2 in T-cells. Our results demonstrate that hSFRP2 mAb treatment inhibits metastases in two metastatic models of OS and can overcome resistance to a PD-1 monoclonal antibody. hSFRP2 mAb treatment restores T-cell proliferation and, in T-cells, inhibits NFATc3, CD38 and PD-1 expression. We conclude that SFRP2-targeted immunotherapy reduces the growth of metastatic osteosarcoma, not only through a direct antitumor and antiangiogenic effect but also by impacting the immune system.
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. View Full-Text
Keywords: SFRP2; CD38; WNT; NFAT; immunotherapy SFRP2; CD38; WNT; NFAT; immunotherapy
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MDPI and ACS Style

Nasarre, P.; Garcia, D.I.; Siegel, J.B.; Bonilla, I.V.; Mukherjee, R.; Hilliard, E.; Chakraborty, P.; Nasarre, C.; Yustein, J.T.; Lang, M.; Jaffa, A.A.; Mehrotra, S.; Klauber-DeMore, N. Overcoming PD-1 Inhibitor Resistance with a Monoclonal Antibody to Secreted Frizzled-Related Protein 2 in Metastatic Osteosarcoma. Cancers 2021, 13, 2696. https://doi.org/10.3390/cancers13112696

AMA Style

Nasarre P, Garcia DI, Siegel JB, Bonilla IV, Mukherjee R, Hilliard E, Chakraborty P, Nasarre C, Yustein JT, Lang M, Jaffa AA, Mehrotra S, Klauber-DeMore N. Overcoming PD-1 Inhibitor Resistance with a Monoclonal Antibody to Secreted Frizzled-Related Protein 2 in Metastatic Osteosarcoma. Cancers. 2021; 13(11):2696. https://doi.org/10.3390/cancers13112696

Chicago/Turabian Style

Nasarre, Patrick; Garcia, Denise I.; Siegel, Julie B.; Bonilla, Ingrid V.; Mukherjee, Rupak; Hilliard, Eleanor; Chakraborty, Paramita; Nasarre, Cécile; Yustein, Jason T.; Lang, Margaret; Jaffa, Aneese A.; Mehrotra, Shikhar; Klauber-DeMore, Nancy. 2021. "Overcoming PD-1 Inhibitor Resistance with a Monoclonal Antibody to Secreted Frizzled-Related Protein 2 in Metastatic Osteosarcoma" Cancers 13, no. 11: 2696. https://doi.org/10.3390/cancers13112696

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