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

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.

Identification immunophenotyping of lung adenocarcinomas based on the tumor microenvironment

“…However, for the patients with Exhausted Immune Class tumors, due to in the tumor microenvironment comprising M2 macrophages, which promote tumor growth, and immunosuppressive factors like TGF-β, the combination of TGF-β and CSF1R inhibitors plus monoclonal antibody agents would be a good therapeutic option. 30,31 For remaining patients, we aim to recruit more immune-related components into the tumor microenvironment combined with immune checkpoint inhibitors against tumor progression, such as MALT1 inhibition by mepazine plus anti-PD-1. 32 In conclusion, our work identifies the novel immunophenotypes in LUAD based on the tumor microenvironment.…”

Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations

“…In murine models of colorectal cancer (CRC), mice receiving a TGFβ inhibitor were resistant to metastatic formation [ 72 ]. However, utilizing TGFβ inhibitors to improve RT efficacy has not consistently induced tumour control due to the complex role played by this cytokine as both a tumour promotor and tumour suppressor [ 68 , 73 ]. RT also stimulates production of chemokines CCL2 and CCL5, which recruit inflammatory monocytes that differentiate into immunosuppressive TAMs in the TME.…”

“…Enhances T-cell infiltration in combination with anti-PD1. Combination with RT and anti-PD1 induced greater responses compared to anti-PD1 alone [ 72 , 73 , 93 , 95 ] PDE5 Inhibitor Increases T cell infiltration and activation by reducing MDSC function. Improved outcomes observed in patients with metastatic melanoma [ 97 , 98 ] …”

TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors

“…TGF-β signaling with a TGF-β1 antibody (19), TGF-βRI inhibitor (20), or overexpressing dominant-negative TGF-βRII have all been shown to enhance the tumor elimination ability of T cells (21,22).…”