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

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Abstract

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-γ 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-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.

Conclusions

Taken 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.

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Most cited references 33

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Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Brian Rini, Elizabeth R Plimack, Viktor P Stus … (2019)

The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.

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Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Robert Motzer, Konstantin Penkov, John Haanen … (2019)

In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.

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Immunogenic cell death in cancer and infectious disease

Lorenzo Galluzzi, Aitziber Buqué, Oliver Kepp … (2016)

Initiation of an adaptive immune response depends on the detection of both antigenic epitopes and adjuvant signals. Infectious pathogens and cancer cells often avoid immune detection by limiting the release of danger signals from dying cells. When is cell death immunogenic and what are the pathophysiological implications of this process?

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Author and article information

Contributors

Darina Ocadlikova: URI : https://loop.frontiersin.org/people/486018

Mariangela Lecciso: URI : https://loop.frontiersin.org/people/486766

Javier Martin Broto: URI : https://loop.frontiersin.org/people/426794

Katia Scotlandi: URI : https://loop.frontiersin.org/people/212129

Michele Cavo: URI : https://loop.frontiersin.org/people/819936

Antonio Curti: URI : https://loop.frontiersin.org/people/50658

Emanuela Palmerini: URI : https://loop.frontiersin.org/people/1016550

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 26 February 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 577766

Affiliations

[1] ¹ IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli” , Bologna, Italy

[2] ² Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna , Bologna, Italy

[3] ³ Virgen del Rocio University Hospital, Institute of Biomedicine Research (IBIS) , Seville, Spain

[4] ⁴ Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli , Bologna, Italy

[5] ⁵ Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli , Bologna, Italy

Author notes

Edited by: Vito Longo, Istituto Nazionale dei Tumori (IRCCS), Italy

Reviewed by: Michele Montrone, Istituto Nazionale dei Tumori (IRCCS), Italy; Susanne Rittig, Charité – Universitätsmedizin Berlin, Germany

*Correspondence: Emanuela Palmerini, emanuela.palmerini3@ 123456unibo.it

†These authors have contributed equally to this work

This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

Article

DOI: 10.3389/fimmu.2021.577766

PMC ID: 7952316

PubMed ID: 33717062

SO-VID: 6b55f576-6196-4b78-bd63-925ca754c59f

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 29 June 2020

Date accepted : 12 January 2021

Page count

Figures: 6, Tables: 0, Equations: 0, References: 34, Pages: 12, Words: 7288

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

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Abstract

Background

Methods

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Most cited references 33

Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma

Immunogenic cell death in cancer and infectious disease

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