Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade

Abstract

BackgroundHigh-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.MethodsThe 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-γ production, before and after nivolumab exposure, were analyzed.ResultsAlong 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-γ. 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 completely abrogated 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-γ-producing effector T cells.ConclusionsTaken together, our in vitro data indicate that the treatment of sarcoma cells with sunitinib can exert significant changes on immune cell subsets toward immune activation, leading to DC-based cross-priming of IFN-γ-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.

Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis

“…In vitro, similar effects have been observed in STS: sunitinib prompted PDL-1 upregulation, dendritic cell maturation and T-cell activation. Furthermore, upregulation of T-reg cells was abrogated [54]. Thus, combination of anti-PD and TKIs may mitigate the VEGF-driven immunosuppressive state of STS.…”

The Prognostic Value and Immune Landscapes of a m6A/m5C/m1A-Related LncRNAs Signature in Head and Neck Squamous Cell Carcinoma

“…Dasatinib is an antagonist of the SRC family of kinases, and may potentially induce T-cell response leading to improved survival of malignant pleural mesothelioma ( Chen et al, 2020 ). Chelerythrine, Tamoxifen, Tanespimycin and Sunitinib have also been shown to have anticancer effects in a variety of cancers ( Heng and Cheah, 2020 ; Wang and Liu, 2020 ; Ocadlikova et al, 2021 ; Su et al, 2021 ). These evidences also indicate the prospect of targeting these two lncRNAs for the treatment of HNSCC.…”

MicroRNA‐519d‐3p antagonizes osteosarcoma resistance against cisplatin by targeting PD‐L1

“…Zheng et al found that the hyperactive STAT3 triggered PD‐L1 expression, while STAT3‐specific inhibitor suppressed PD‐L1, leading to the growth reduction of osteosarcoma cells 28 . Darina et al reported that vascular endothelial growth factor and platelet‐derived growth factor‐specific inhibitor sunitinib synergized with PD‐L1 antibody nivolumab, interrupting osteosarcoma progression 29 . Liu et al revealed that miR‐200a rescued PD‐L1 expression from PTEN, enhancing osteosarcoma malignancies 13 .…”