Ludwig, Nils and Wieteska, Lukasz and Hinck, Cynthia S. and Yerneni, Saigopalakrishna S. and Azambuja, Juliana H. and Bauer, Richard J. and Reichert, Torsten E. and Hinck, Andrew P. and Whiteside, Theresa L. (2021) Novel TGF beta Inhibitors Ameliorate Oral Squamous Cell Carcinoma Progression and Improve the Antitumor Immune Response of Anti-PD-L1 Immunotherapy. MOLECULAR CANCER THERAPEUTICS, 20 (6). pp. 1102-1111. ISSN 1535-7163, 1538-8514
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CANCER; EXPRESSION; TGF-BETA-1; BLOCKADE; EVASION; HEAD; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Mund-, Kiefer- und Gesichtschirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Sep 2022 10:53 |
| Last Modified: | 09 Sep 2022 10:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46925 |
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