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Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models

1
Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
2
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(4), 320; https://doi.org/10.3390/cells8040320
Received: 5 March 2019 / Revised: 27 March 2019 / Accepted: 28 March 2019 / Published: 5 April 2019
(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)
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Abstract

Antibodies blocking the programmed death-ligand 1 (PD-L1) have shown impressive and durable responses in clinical studies. However, this type of immunotherapy is only effective in a subset of patients and not sufficient for rejection of all tumor types. In this study, we explored in two mouse tumor models whether the antitumor effect could be enhanced by the combined blockade of PD-L1 and transforming growth factor-β (TGF-β), a potent immunosuppressive cytokine. The effect of anti-PD-L1 mouse monoclonal (mAb) and a TGF-β type I receptor small molecule kinase inhibitor (LY364947) was evaluated in the highly immunogenic mouse MC38 colon adenocarcinoma and the poorly immunogenic mouse KPC1 pancreatic tumor model. In the MC38 tumor model, LY364947 monotherapy did not show any antitumor effect, whereas treatment with anti-PD-L1 mAb significantly delayed tumor outgrowth. However, combination therapy showed the strongest therapeutic efficacy, resulting in improved long-term survival compared with anti-PD-L1 mAb monotherapy. This improved survival was associated with an increased influx of CD8+ T cells in the tumor microenvironment. In the KPC1 tumor model, LY364947 did not enhance the antitumor effect of anti-PD-L1 mAb. Despite this, delayed KPC1 tumor outgrowth was observed in the LY364947-treated group and this treatment led to a significant reduction of CD4+ T cells in the tumor microenvironment. Together, our data indicate that an additive anti-tumor response of dual targeting PD-L1 and TGF-β is dependent on the tumor model used, highlighting the importance of selecting appropriate cancer types, using in-depth analysis of the tumor microenvironment, which can benefit from combinatorial immunotherapy regimens. View Full-Text
Keywords: anti-PD-L1 mAb 1; LY364947 2; mouse syngeneic tumor models 3 anti-PD-L1 mAb 1; LY364947 2; mouse syngeneic tumor models 3
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Sow, H.S.; Ren, J.; Camps, M.; Ossendorp, F.; ten Dijke, P. Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models. Cells 2019, 8, 320.

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