2. Academic Validation
  3. FXR shapes an immunosuppressive microenvironment in PD-L1lo/- non-small cell lung cancer by upregulating HVEM

FXR shapes an immunosuppressive microenvironment in PD-L1lo/- non-small cell lung cancer by upregulating HVEM

  • JCI Insight. 2025 Sep 23;10(18):e190716. doi: 10.1172/jci.insight.190716.
Xiaolong Xu 1 2 3,  Bin Shang 4 5 6 7,  Hancheng Wu 1 2 6 7,  Xiuye Jin 1 2 8,  Junren Wang 1 2 6 7,  Jing Li 9,  Daowei Li 1 2 6 7,  Bin Liang 1 2 6 7,  Xingguang Wang 1 2 6 7,  Lili Su 1 2 6 7,  Wenjie You 1 2 6 7 10,  Shujuan Jiang 1 2 6 7
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 2 Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
  • 3 Department of Respiratory and Critical Care Medicine, the Second Hospital of Shandong University, Jinan, Shandong, China.
  • 4 Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 5 Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
  • 6 Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, Shandong, China.
  • 7 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 8 Department of Respiratory and Critical Care Medicine, Xi'an Chest Hospital, Shanxi, China.
  • 9 Department of Respiratory and Critical Care Medicine, Shandong Provincial Public Health Clinical Center, Jinan, Shandong, China.
  • 10 Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.
PMID: 40985894 DOI: 10.1172/jci.insight.190716
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.

Keywords

Cancer immunotherapy; Immunology; Lung cancer; Oncology.

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