RT Journal Article
T1 Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade
A1 Ocadlikova, Darina
A1 Lecciso, Mariangela
A1 Broto, Javier Martin
A1 Scotlandi, Katia
A1 Cavo, Michele
A1 Curti, Antonio
A1 Palmerini, Emanuela
K1 Osteosarcoma
K1 Synovial sarcoma
K1 Tyrosine kinase inhibitor (TKI)
K1 Nivolumab
K1 Sunitinib
K1 Immunomodulation
K1 Dendritic cell (DC)
K1 T regulatory cells
K1 Sarcoma sinovial
K1 Inmunomodulación
K1 Células dendríticas
K1 Linfocitos T reguladores
AB Background: High-grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. After relapse, treatment options are limited. The multi targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and inhibitor of PD-1 (anti-PD 1) nivolumab have shown antitumor activity in selected subtypes. In this study, we examine the role of TKIs and PD-1 based therapy in in vitro cocultures of sarcoma. Methods: The human osteosarcoma (SaOS-2) and synovial sarcoma (SYO-1) cell lines were treated with sunitinib. After cell death and proliferation assessment, expression of PD-L1 was analyzed by flow cytometry. Sunitinib-treated sarcoma cells were cocultured with dendritic cells (DCs), and the phenotype of mature DCs was determined by flow cytometry. Mature DCs were cultured with autologous T cells. PD-1 expression on T cells, their proliferation, T regulatory cell (Tregs) induction and IFN-g production, before and after nivolumab exposure, were analyzed. Results: Along with its anti-proliferative and direct pro-apoptotic effect on sarcoma cell lines, sunitinib prompted PD-L1 upregulation on sarcoma cells. Interestingly, sunitinib treated sarcoma cells drive DCs to full maturation and increase their capacity to induce sarcoma-reactive T cells to produce IFN-g. Conversely, no effect on T cell proliferation and T cell subpopulation composition was observed. Moreover, both bone and synovial sarcoma cell lines induced Tregs through DCs but sunitinib treatment completelyabrogated Treg induction. Finally, sarcoma cell lines induced PD-1 upregulation on both effector T cells and Tregs when loaded into DCs, providing a rationale for using PD-1 blockade. Indeed, PD-1 blockade by nivolumab synergized with sunitinib in inducing IFN-g-producing effector T cells. Conclusions: Taken together, our in vitro data indicate that the treatment of sarcomacells with sunitinib can exert significant changes on immune cell subsets toward immune activation, leading to DC-based cross-priming of IFN-g-producing effector T cells and reduced Treg induction. PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD-1 approach in sarcomas, and perhaps in other cancers. DC-targeted drugs, including toll-like receptor 3 inhibitors and CD47 inhibitors, are under development and our preclinical model might help to better design their clinical application.
PB Frontiers
YR 2021
FD 2021-02-25
LK http://hdl.handle.net/10668/4011
UL http://hdl.handle.net/10668/4011
LA en
NO Ocadlikova D, Lecciso M, Broto JM, Scotlandi K, Cavo M, Curti A, et al. Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade. Front Immunol. 2021 Feb 26;12:577766
DS RISalud
RD Apr 7, 2025