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.
Highlights
Immune checkpoint molecules are gaining prominence as targets for cancer immunotherapy, demonstrating durable remission of patients with metastatic lesions [1]
In order to select mouse tumor models to investigate the therapeutic efficacy of combining transforming growth factor-β (TGF-β) inhibitor and anti-programmed death ligand 1 (PD-L1) mAb, we measured mTGF-β1 production by various mouse tumor cell lines
Using a transcriptional reporter assay, we observed that MC38 but not KPC1 cells secreted elevated amounts of active mTGF-β (Figure 1B)
Summary
Immune checkpoint molecules are gaining prominence as targets for cancer immunotherapy, demonstrating durable remission of patients with metastatic lesions [1]. Together with other cytokines such as interleukin (IL)-2 and IL-6, TGF-β induces the generation and recruitment of regulatory T cells to further suppress the antitumor T and NK cell responses [21,22]. It is known for its role in regulating and promoting the accumulation of stiff fibrillary extracellular matrix composed of collagen [23], resulting in hindered drug transport [24] and infiltration of immune cells [25,26,27] into the tumor. LY364947 [33], can enhance the antitumor efficacy of anti-PD-L1 mAb in immunogenic (MC38 colorectal tumor) and poorly immunogenic (KPC1 pancreatic tumor) tumor models
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