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Laminin γ2-mediating T cell exclusion attenuates response to anti-PD-1 therapy
Lei Li1,2,3, Jia-Ru Wei4, Jun Dong5
1State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. xyguan@hku.hk lilei728@hku.hk.
Abstract:
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 γ2 (Ln-γ2) 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-γ2 was transcriptionally activated by transforming growth factor-β1 (TGF-β1) 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-β receptor inhibitor galunisertib and chemotherapy drugs provoked vigorous antitumor activity of anti-PD-1 therapy in mouse tumor models. Therefore, Ln-γ2 may represent a useful biomarker to optimize clinical decisions and predict the response of cancer patients to treatment with anti-PD-1 drugs.
Insights
Laminin γ2 (Ln-γ2) up-regulation predicts reduced anti-PD-1 therapy effectiveness in lung and esophageal cancers. Targeting TGF-β1 signaling with galunisertib may enhance anti-PD-1 treatment efficacy.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- PD-1/PD-L1 blockade offers clinical benefits in advanced cancers.
- Factors influencing anti-PD-1 therapy efficacy are not fully understood.
Purpose of the Study:
- To identify biomarkers predicting anti-PD-1 therapy response.
- To investigate the role of laminin γ2 (Ln-γ2) in anti-PD-1 efficacy.
Main Methods:
- Analysis of Ln-γ2 expression in lung and esophageal cancer patients.
- Investigated TGF-β1 signaling pathway activation by cancer-associated fibroblasts.
- Assessed the impact of Ln-γ2 on T cell infiltration.
- Evaluated coadministration of TGF-β receptor inhibitor galunisertib and anti-PD-1 therapy in mouse models.
Main Results:
- Elevated Ln-γ2 levels correlated with decreased anti-PD-1 efficacy and poorer patient outcomes.
- Ln-γ2 was transcriptionally activated by TGF-β1 via JNK/AP1 signaling.
- Ln-γ2 hindered T cell infiltration by modulating T cell receptor expression.
- Combined galunisertib and chemotherapy enhanced anti-PD-1 therapy in preclinical models.
Conclusions:
- Ln-γ2 is a potential biomarker for predicting anti-PD-1 therapy response.
- Targeting TGF-β1 signaling alongside anti-PD-1 therapy could improve cancer treatment outcomes.
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