TY - JOUR
T1 - Novel TGFb inhibitors ameliorate oral squamous cell carcinoma progression and improve the antitumor immune response of anti-PD-L1 immunotherapy
AU - Ludwig, Nils
AU - Wieteska, Łukasz
AU - Hinck, Cynthia S.
AU - Yerneni, Saigopalakrishna S.
AU - Azambuja, Juliana H.
AU - Bauer, Richard J.
AU - Reichert, Torsten E.
AU - Hinck, Andrew P.
AU - Whiteside, Theresa L.
N1 - Funding Information:
This work was supported by NIH grant U01-DE029759 to T.L. Whiteside, RO1 CA172886 to A.P. Hinck and Dr. LuZhe Sun (University of Texas Health Science Center, San Antonio, TX), and RO1 GM58670 to A.P. Hinck. N. Ludwig was supported by the Leopoldina Fellowships LPDS 2017-12 and LPDR 2019-02 from German National Academy of Sciences Leopoldina and the young investigator award from Freier Verband Deutscher Zahn€arzte e.V. (FVDZ). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skøodowska-Curie grant agreement No 893196 to Ł. Wieteska.
Funding Information:
This work was supported by NIH grant U01-DE029759 to T.L. Whiteside, RO1 CA172886 to A.P. Hinck and Dr. LuZhe Sun (University of Texas Health Science Center, San Antonio, TX), and RO1 GM58670 to A.P. Hinck. N. Ludwig was supported by the Leopoldina Fellowships LPDS 2017-12 and LPDR 2019-02 from German National Academy of Sciences Leopoldina and the young investigator award from Freier Verband Deutscher Zahn€arzte e.V. (FVDZ). This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skøodowska-Curie grant agreement No 893196 to Ł. Wieteska.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6
Y1 - 2021/6
N2 - TGFb 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 TGFb inhibitors as mono or combinatorial therapy with anti-PD-L1 antibodies (a-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 TGFb inhibitors mRER (i.p., 50 mg/d) or mmTGFb2-7m (10 mg/d delivered by osmotic pumps) alone or in combination with a-PD-L1 Abs (7 x i.p. of 100 mg/72 h). Tumor progression and body weight were monitored. Levels of bioactive TGFb in serum were quantified using a TGFb bioassay. Tissues were analyzed by immunohistology and flow cytometry. Therapy with mRER or mmTGFb2-7m reduced tumor burden (P < 0.05) and decreased body weight loss compared with controls. In inhibitor-treated mice, levels of TGFb in tumor tissue and serum were reduced (P < 0.05), whereas they increased with tumor progression in controls. Both inhibitors enhanced CD8þ T-cell infiltration into tumors and mRER reduced levels of myeloid-derived suppressor cells (P < 0.001). In combination with a-PD-L1 Abs, tumor burden was not further reduced; however, mmTGFb2-7m further reduced weight loss (P < 0.05). The collagen-rich stroma was reduced by using combinatorial TGFb/PD-L1 therapies (P < 0.05), enabling an accelerated lymphocyte infiltration into tumor tissues. The blockade of TGFb signaling by mRER or mmTGFb2-7m ameliorated in vivo progression of established murine OSCC. The inhibitors promoted antitumor immune responses, alone and in combination with a-PD-L1 Abs.
AB - TGFb 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 TGFb inhibitors as mono or combinatorial therapy with anti-PD-L1 antibodies (a-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 TGFb inhibitors mRER (i.p., 50 mg/d) or mmTGFb2-7m (10 mg/d delivered by osmotic pumps) alone or in combination with a-PD-L1 Abs (7 x i.p. of 100 mg/72 h). Tumor progression and body weight were monitored. Levels of bioactive TGFb in serum were quantified using a TGFb bioassay. Tissues were analyzed by immunohistology and flow cytometry. Therapy with mRER or mmTGFb2-7m reduced tumor burden (P < 0.05) and decreased body weight loss compared with controls. In inhibitor-treated mice, levels of TGFb in tumor tissue and serum were reduced (P < 0.05), whereas they increased with tumor progression in controls. Both inhibitors enhanced CD8þ T-cell infiltration into tumors and mRER reduced levels of myeloid-derived suppressor cells (P < 0.001). In combination with a-PD-L1 Abs, tumor burden was not further reduced; however, mmTGFb2-7m further reduced weight loss (P < 0.05). The collagen-rich stroma was reduced by using combinatorial TGFb/PD-L1 therapies (P < 0.05), enabling an accelerated lymphocyte infiltration into tumor tissues. The blockade of TGFb signaling by mRER or mmTGFb2-7m ameliorated in vivo progression of established murine OSCC. The inhibitors promoted antitumor immune responses, alone and in combination with a-PD-L1 Abs.
UR - http://www.scopus.com/inward/record.url?scp=85106999760&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106999760&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-20-0944
DO - 10.1158/1535-7163.MCT-20-0944
M3 - Article
C2 - 33850003
AN - SCOPUS:85106999760
VL - 20
SP - 1102
EP - 1111
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 6
ER -