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Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors

Cancer-associated fibroblasts (CAFs) has been recognized as one cause of tumor resistance to immune checkpoint blockade therapy, but the underlying mechanisms still remain elusive. In the present study, a bone marrow-derived CAF (BMF) -rich tumor model is successfully established by subcutaneously m...

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Autores principales: Huang, Tinglei, Li, Fuli, Cheng, Xiaojiao, Wang, Jianzheng, Zhang, Wenhui, Zhang, Baiwen, Tang, Yao, Li, Qingli, Zhou, Cong, Tu, Shuiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006364/
https://www.ncbi.nlm.nih.gov/pubmed/33790893
http://dx.doi.org/10.3389/fimmu.2021.619209
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author Huang, Tinglei
Li, Fuli
Cheng, Xiaojiao
Wang, Jianzheng
Zhang, Wenhui
Zhang, Baiwen
Tang, Yao
Li, Qingli
Zhou, Cong
Tu, Shuiping
author_facet Huang, Tinglei
Li, Fuli
Cheng, Xiaojiao
Wang, Jianzheng
Zhang, Wenhui
Zhang, Baiwen
Tang, Yao
Li, Qingli
Zhou, Cong
Tu, Shuiping
author_sort Huang, Tinglei
collection PubMed
description Cancer-associated fibroblasts (CAFs) has been recognized as one cause of tumor resistance to immune checkpoint blockade therapy, but the underlying mechanisms still remain elusive. In the present study, a bone marrow-derived CAF (BMF) -rich tumor model is successfully established by subcutaneously mixed inoculation of BMFs and tumor cells into mice and the BMF-mixed tumor xenografts are demonstrated to be resistant to anti-PD-L1 antibody immunotherapy compared to the mere tumor xenografts. In vitro assays via the co-culture system of BMFs and tumor cells indicate that the co-cultured BMFs are induced to overexpress PD-L1, while there is no such a phenomenon in the co-cultured cancer cells. The further knock-out of PD-L1 in BMFs rescues the sensitivity of BMF-mixed tumor xenografts to PD-L1 blockade therapy. Mechanistically, via the microarray assay, we identify that the upregulation of PD-L1 in BMFs stimulated by cancer cells is medicated by the activation of the Wnt/β-catenin signaling pathway in BMFs. Moreover, the administration of Wnt/β-catenin signaling inhibitors, including XAV-939 and Wnt-C59, distinctly inhibits the upregulation of PD-L1 expression in the co-cultured BMFs. The further combination administration of XAV-939 significantly potentiates the therapeutic outcome of PD-L1 blockade therapy in BMF-mixed tumors. In summary, our study demonstrates that Wnt inhibition augments PD-L1 blockade efficacy by overcoming BMF-mediated immunotherapy resistance.
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spelling pubmed-80063642021-03-30 Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors Huang, Tinglei Li, Fuli Cheng, Xiaojiao Wang, Jianzheng Zhang, Wenhui Zhang, Baiwen Tang, Yao Li, Qingli Zhou, Cong Tu, Shuiping Front Immunol Immunology Cancer-associated fibroblasts (CAFs) has been recognized as one cause of tumor resistance to immune checkpoint blockade therapy, but the underlying mechanisms still remain elusive. In the present study, a bone marrow-derived CAF (BMF) -rich tumor model is successfully established by subcutaneously mixed inoculation of BMFs and tumor cells into mice and the BMF-mixed tumor xenografts are demonstrated to be resistant to anti-PD-L1 antibody immunotherapy compared to the mere tumor xenografts. In vitro assays via the co-culture system of BMFs and tumor cells indicate that the co-cultured BMFs are induced to overexpress PD-L1, while there is no such a phenomenon in the co-cultured cancer cells. The further knock-out of PD-L1 in BMFs rescues the sensitivity of BMF-mixed tumor xenografts to PD-L1 blockade therapy. Mechanistically, via the microarray assay, we identify that the upregulation of PD-L1 in BMFs stimulated by cancer cells is medicated by the activation of the Wnt/β-catenin signaling pathway in BMFs. Moreover, the administration of Wnt/β-catenin signaling inhibitors, including XAV-939 and Wnt-C59, distinctly inhibits the upregulation of PD-L1 expression in the co-cultured BMFs. The further combination administration of XAV-939 significantly potentiates the therapeutic outcome of PD-L1 blockade therapy in BMF-mixed tumors. In summary, our study demonstrates that Wnt inhibition augments PD-L1 blockade efficacy by overcoming BMF-mediated immunotherapy resistance. Frontiers Media S.A. 2021-03-15 /pmc/articles/PMC8006364/ /pubmed/33790893 http://dx.doi.org/10.3389/fimmu.2021.619209 Text en Copyright © 2021 Huang, Li, Cheng, Wang, Zhang, Zhang, Tang, Li, Zhou and Tu http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Huang, Tinglei
Li, Fuli
Cheng, Xiaojiao
Wang, Jianzheng
Zhang, Wenhui
Zhang, Baiwen
Tang, Yao
Li, Qingli
Zhou, Cong
Tu, Shuiping
Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors
title Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors
title_full Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors
title_fullStr Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors
title_full_unstemmed Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors
title_short Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors
title_sort wnt inhibition sensitizes pd-l1 blockade therapy by overcoming bone marrow-derived myofibroblasts-mediated immune resistance in tumors
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006364/
https://www.ncbi.nlm.nih.gov/pubmed/33790893
http://dx.doi.org/10.3389/fimmu.2021.619209
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