FXR shapes an immunosuppressive microenvironment in PD-L1^lo/– non-small cell lung cancer by upregulating HVEM

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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.

Authors

Xiaolong Xu, Bin Shang, Hancheng Wu, Xiuye Jin, Junren Wang, Jing Li, Daowei Li, Bin Liang, Xingguang Wang, Lili Su, Wenjie You, Shujuan Jiang