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FXR shapes an immunosuppressive microenvironment in PD-L1lo/- non-small cell lung cancer by upregulating HVEM
Xiaolong Xu1,2,3, Bin Shang4,5,6,7, Hancheng Wu1,2,6,7
1Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China.
Abstract:
Immune checkpoint therapy has changed cancer treatment, including non-small cell lung cancer (NSCLC). The unresponsiveness of PD-L1lo/- tumors to anti-PD-1/PD-L1 immunotherapy is attributed to alternative immune evasion mechanisms that remain elusive. We previously reported that farnesoid X receptor (FXR) was increased in PD-L1lo/- NSCLC. Herein, we found that immune checkpoint HVEM was positively correlated with FXR but inversely correlated with PD-L1 in NSCLC. HVEM was highly expressed in FXRhiPD-L1lo NSCLC. Consistently, clinically relevant FXR antagonist dose-dependently inhibited HVEM expression in NSCLC. FXR inhibited cytokine production and cytotoxicity of cocultured CD8+ T cells in vitro, and it shaped an immunosuppressive tumor microenvironment (TME) in mouse tumors in vivo through the HVEM/BTLA pathway. Clinical investigations show that the FXR/HVEM axis was associated with immunoevasive TME and inferior survival outcomes in patients with NSCLC. Mechanistically, FXR upregulated HVEM via transcriptional activation, intracellular Akt, Erk1/2 and STAT3 signals, and G1/S cycle progression in NSCLC cells. In vivo treatment experiments demonstrated that anti-BTLA immunotherapy reinvigorated antitumor immunity in TME, resulting in enhanced tumor inhibition and survival improvement in FXRhiPD-L1lo mouse Lewis lung carcinomas. In summary, our findings establish the FXR/HVEM axis as an immune evasion mechanism in PD-L1lo/- NSCLC, providing translational implications for future immunotherapy in this subgroup of patients.
Insights
Farnesoid X receptor (FXR) drives immune evasion in non-small cell lung cancer (NSCLC) by upregulating HVEM, hindering anti-PD-1/PD-L1 therapy. Targeting the FXR/HVEM axis with anti-BTLA immunotherapy shows promise for treating these resistant tumors.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) like anti-PD-1/PD-L1 have transformed cancer treatment, yet many non-small cell lung cancer (NSCLC) patients remain unresponsive.
- Alternative immune evasion mechanisms in PD-L1 low/negative (PD-L1lo/-) NSCLC are not fully understood, limiting therapeutic efficacy.
- Previous research identified increased farnesoid X receptor (FXR) in PD-L1lo/- NSCLC.
Purpose of the Study:
- To investigate the role of FXR in immune evasion within NSCLC, particularly in tumors unresponsive to PD-1/PD-L1 therapy.
- To elucidate the molecular mechanisms by which FXR contributes to an immunosuppressive tumor microenvironment (TME).
- To evaluate the therapeutic potential of targeting the identified FXR-mediated immune evasion pathway.
Main Methods:
- Correlative analysis of FXR, HVEM, and PD-L1 expression in NSCLC patient samples.
- In vitro studies assessing the impact of FXR on CD8+ T cell function and cytokine production.
- In vivo experiments using mouse models to evaluate the FXR/HVEM axis and test anti-BTLA immunotherapy.
- Mechanistic studies involving transcriptional regulation, signaling pathways (Akt, Erk1/2, STAT3), and cell cycle analysis.
Main Results:
- A positive correlation was observed between FXR and immune checkpoint HVEM, and an inverse correlation between FXR and PD-L1 in NSCLC.
- FXR was highly expressed in FXR-high/PD-L1-low (FXRhiPD-L1lo) NSCLC and was shown to inhibit CD8+ T cell activity.
- FXR upregulated HVEM expression via transcriptional control and signaling pathways, promoting an immunosuppressive TME.
- Targeting the HVEM/BTLA pathway with anti-BTLA immunotherapy effectively inhibited tumor growth and improved survival in preclinical models.
Conclusions:
- The FXR/HVEM axis represents a novel immune evasion mechanism in PD-L1lo/- NSCLC, contributing to therapeutic resistance.
- Targeting this axis offers a promising strategy to overcome resistance to current immunotherapies in a subset of NSCLC patients.
- These findings have significant translational implications for developing novel combination therapies for NSCLC.
