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

TGFβ 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 TGFβ inhibitors as mono or combinatorial therapy with anti-PD-L1 antibodies (α-PD-L1 Ab) in a murine...

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Published in:Molecular cancer therapeutics 2021-06, Vol.20 (6), p.1102-1111
Main Authors: Ludwig, Nils, Wieteska, Łukasz, Hinck, Cynthia S, Yerneni, Saigopalakrishna S, Azambuja, Juliana H, Bauer, Richard J, Reichert, Torsten E, Hinck, Andrew P, Whiteside, Theresa L
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - pathology
Disease Progression
Humans
Immune Checkpoint Inhibitors - pharmacology
Immune Checkpoint Inhibitors - therapeutic use
Immunotherapy - methods
Longitudinal Studies
Mice
Mouth Neoplasms - drug therapy
Mouth Neoplasms - pathology
Transforming Growth Factor beta - antagonists & inhibitors
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Summary:TGFβ 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 TGFβ inhibitors as mono or combinatorial therapy with anti-PD-L1 antibodies (α-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 TGFβ inhibitors mRER (i.p., 50 μg/d) or mmTGFβ2-7m (10 μg/d delivered by osmotic pumps) alone or in combination with α-PD-L1 Abs (7× i.p. of 100 μg/72 h). Tumor progression and body weight were monitored. Levels of bioactive TGFβ in serum were quantified using a TGFβ bioassay. Tissues were analyzed by immunohistology and flow cytometry. Therapy with mRER or mmTGFβ2-7m reduced tumor burden ( < 0.05) and decreased body weight loss compared with controls. In inhibitor-treated mice, levels of TGFβ in tumor tissue and serum were reduced ( < 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 ( < 0.001). In combination with α-PD-L1 Abs, tumor burden was not further reduced; however, mmTGFβ2-7m further reduced weight loss ( < 0.05). The collagen-rich stroma was reduced by using combinatorial TGFβ/PD-L1 therapies ( < 0.05), enabling an accelerated lymphocyte infiltration into tumor tissues. The blockade of TGFβ signaling by mRER or mmTGFβ2-7m ameliorated progression of established murine OSCC. The inhibitors promoted antitumor immune responses, alone and in combination with α-PD-L1 Abs.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-20-0944