Advancements in TGF-β Targeting Therapies for Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy.

Keywords: BCA-101; LY3200882; SHR-1701; TGF-β; bintrafusp alfa; dalantercept; epithelial-to-mesenchymal transition; head and neck squamous cell carcinoma.

Figure 1

The schematic depicts canonical and non-canonical TGF-β signaling influencing EMT. Upon binding to its receptor, TBRII forms a heterotetrameric complex leading to the phosphorylation of TBRI. This induces canonical signaling, in which SMAD-related proteins lead to the transcription of SNAIL-1, which either inhibits the transcription of E-Cadherin or promotes the transcription of MMP-9. The transcription of MMP-9 is also promoted through a non-canonical pathway in which ERK1/2 signaling-induced SNAIL2 (SLUG) transcription further augments MMP-9 transcription.

Figure 2

TGF-β influences the immune–tumor interface to create a pro-oncogenic TME through its action on tumor-associated neutrophils, monocytes, dendritic cells, and lymphocytes. This action promotes tumor growth and angiogenesis and suppresses the immune-related detection and destruction of tumor cells.

Figure 3

This schematic reflects TGF-β signaling pathways which influence angiogenesis. TGF-β may either have a pro-angiogenic or anti-angiogenic influence on cancer. TGF-β or BMP-9/10 attach to ALK-1 or BMPRII, respectively. Downstream SMAD-1, -5, and-8 related signaling coupled with SMAD-4 leads to the transcription of ID1, which promotes endothelial cell proliferation and migration. Conversely, TGF-β can also bind to an ALK-5 receptor. This initiates downstream signaling with Smad-2 and Smad-3, which similarly couple with Smad-4. However, this complex translocates to the nucleus and leads to the transcription of PAI-1, promoting vessel maturation.

Figure 4

Both bintrafusp alfa and SHR-1701 consist of an IgG1 anti-PD-L1 component fused to the extracel-lular domain of TGF-BRII. These therapies function by competitively inhibiting the PD-L1 receptor on tumor cells and by binding serum circulating TGF-β to reduce TGF-β-related signaling.