Novel TGF beta Inhibitors Ameliorate Oral Squamous Cell Carcinoma Progression and Improve the Antitumor Immune Response of Anti-PD-L1 Immunotherapy

TGF beta is a key regulator of oral squamous cell carcinoma (OSCC) progression, and its potential role as a therapeutic target has been investigated with a limited success. This study evaluates two novel TGF beta inhibitors as mono or combinatorial therapy with anti-PD-L1 antibodies (alpha-PD-L1 Ab) in a murine OSCC model. Immunocompetent C57BL/6 mice bearing malignant oral lesions induced by 4-nitroquinoline 1-oxide (4-NQO) were treated for 4 weeks with TGF beta inhibitors mRER (i.p., 50 mu g/d) or mmTGF beta 2-7m (10 mg/d delivered by osmotic pumps) alone or in combination with alpha-PD-L1 Abs (7x i.p. of 100 mu g/72 h). Tumor progression and body weight were monitored. Levels of bioactive TGF beta in serum were quantified using a TGF beta bioassay. Tissues were analyzed by immunohistology and flow cytometry. Therapy with mRER or mmTGF beta 2-7m reduced tumor burden (P < 0.05) and decreased body weight loss compared with controls. In inhibitor-treated mice, levels of TGF beta in tumor tissue and serum were reduced (P < 0.05), whereas they increased with tumor progression in controls. Both inhibitors enhanced CD8(+) T-cell infiltration into tumors and mRER reduced levels of myeloid-derived suppressor cells (P < 0.001). In combination with alpha-PD-L1 Abs, tumor burden was not further reduced; however, mmTGF beta 2-7m further reduced weight loss (P < 0.05). The collagen-rich stroma was reduced by using combinatorial TGF beta/PD-L1 therapies (P < 0.05), enabling an accelerated lymphocyte infiltration into tumor tissues. The blockade of TGF beta signaling by mRER or mmTGF beta 2-7m ameliorated in vivo progression of established murine OSCC. The inhibitors promoted antitumor immune responses, alone and in combination with alpha-PD-L1 Abs.

Automated summary

This study found that two novel TGF beta inhibitors can reduce tumor burden and decrease body weight loss in a murine oral squamous cell carcinoma (OSCC) model, and enhance CD8(+) T-cell infiltration into tumors. Combination therapy with PD-L1 antibodies further reduces weight loss and accelerates lymphocyte infiltration into tumor tissues.