期刊
SCIENCE ADVANCES
卷 7, 期 6, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abc8346
关键词
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资金
- National Natural Science Foundation of China [81772554, 81871903, 82072604, 82072738]
- China National Key Sci-Tech Special Project of Infectious Diseases [2018ZX10723204-006005]
- National Science Foundation for Young Scholars of China [81601581, 81600606]
- Basic and Applied Basic Research Foundation of Guangdong Province [2019A1515110660]
- National Science Foundation of Guangdong Province [2017A030313764]
- Hong Kong Research Grant Council General Research Funds [HKU/7668/11M, 767313, 17143716]
- Hong Kong Theme-based Research Scheme Fund [T12-704/16-R]
- Hong Kong Research Grant Council Collaborative Research Funds [C7065-18GF, C7026-18GF]
- Shenzhen Fundamental Research Program [KQDT2015033117210153]
PD-1/PD-L1 blockade therapies have shown significant clinical benefits for advanced cancer patients, but the effectiveness of treatment can be hindered by the up-regulation of laminin gamma 2 (Ln-gamma 2) in the tumor microenvironment, which is transcriptionally activated by transforming growth factor-beta 1 (TGF-beta 1) through JNK/AP1 signaling. Co-administration of a TGF-beta receptor inhibitor and chemotherapy drugs can enhance the anti-tumor activity of anti-PD-1 therapy.
PD-1/PD-L1 blockade therapies provide notable clinical benefits for patients with advanced cancers, but the factors influencing the effectiveness of the treatment remain incompletely cataloged. Here, the up-regulation of laminin gamma 2 (Ln-gamma 2) predicted the attenuated efficacy of anti-PD-1 drugs and was associated with unfavorable outcomes in patients with lung cancer or esophageal cancer. Furthermore, Ln-gamma 2 was transcriptionally activated by transforming growth factor-beta 1 (TGF-beta 1) secreted from cancer-associated fibroblasts via JNK/AP1 signaling, which blocked T cell infiltration into the tumor nests by altering the expression of T cell receptors. Coadministration of the TGF-beta receptor inhibitor galunisertib and chemotherapy drugs provoked vigorous antitumor activity of anti-PD-1 therapy in mouse tumor models. Therefore, Ln-gamma 2 may represent a useful biomarker to optimize clinical decisions and predict the response of cancer patients to treatment with anti-PD-1 drugs.
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