Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models
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...
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MDPI AG
2019-04-01
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| author | Heng Sheng Sow Jiang Ren Marcel Camps Ferry Ossendorp Peter ten Dijke |
| author_facet | Heng Sheng Sow Jiang Ren Marcel Camps Ferry Ossendorp Peter ten Dijke |
| author_sort | Heng Sheng Sow |
| collection | DOAJ |
| description | 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<sup>+</sup> 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<sup>+</sup> 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. |
| first_indexed | 2024-03-12T07:09:53Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T07:09:53Z |
| publishDate | 2019-04-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-1ca01e7ec3cd48e7ba16b6b606177fbb2023-09-02T23:08:45ZengMDPI AGCells2073-44092019-04-018432010.3390/cells8040320cells8040320Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor ModelsHeng Sheng Sow0Jiang Ren1Marcel Camps2Ferry Ossendorp3Peter ten Dijke4Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsDepartment of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The NetherlandsAntibodies 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<sup>+</sup> 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<sup>+</sup> 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.https://www.mdpi.com/2073-4409/8/4/320anti-PD-L1 mAb 1LY364947 2mouse syngeneic tumor models 3 |
| spellingShingle | Heng Sheng Sow Jiang Ren Marcel Camps Ferry Ossendorp Peter ten Dijke Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models Cells anti-PD-L1 mAb 1 LY364947 2 mouse syngeneic tumor models 3 |
| title | Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models |
| title_full | Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models |
| title_fullStr | Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models |
| title_full_unstemmed | Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models |
| title_short | Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models |
| title_sort | combined inhibition of tgf β signaling and the pd l1 immune checkpoint is differentially effective in tumor models |
| topic | anti-PD-L1 mAb 1 LY364947 2 mouse syngeneic tumor models 3 |
| url | https://www.mdpi.com/2073-4409/8/4/320 |
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