FXR agonist GW4064 enhances anti-PD-L1 immunotherapy in colorectal cancer

ABSTRACT

Colorectal cancer (CRC) is one of the top three malignant tumors in terms of morbidity, and the limited efficacy of existing therapies urges the discovery of potential treatment strategies. Immunotherapy gradually becomes a promising cancer treatment method in recent decades; however, less than 10% of CRC patients could really benefit from immunotherapy. It is pressing to explore the potential combination therapy to improve the immunotherapy efficacy in CRC patients. It is reported that Farnesoid X receptor (FXR) is deficiency in CRC and associated with immunity. Herein, we found that GW4064, a FXR agonist, could induce apoptosis, block cell cycle, and mediate immunogenic cell death (ICD) of CRC cells in vitro. Disappointingly, GW4064 could not suppress the growth of CRC tumors in vivo. Further studies revealed that GW4064 upregulated PD-L1 expression in CRC cells via activating FXR and MAPK signaling pathways. Gratifyingly, the combination of PD-L1 antibody with GW4064 exhibited excellent anti-tumor effects in CT26 xenograft models and increased CD8⁺ T cells infiltration, with 33% tumor bearing mice cured. This paper illustrates the potential mechanisms of GW4064 to upregulate PD-L1 expression in CRC cells and provides important data to support the combination therapy of PD-L1 immune checkpoint blockade with FXR agonist for CRC patients.

KEYWORDS:

• Colorectal cancer
• farnesoid X receptor
• GW4064
• PD-L1

Authors’ contributions

Material preparation and data collection were performed by Lu Lu, Yi-Xin Jiang, and Xiao-Xia Liu. Wen-Jie Gu and Jin-Mei Jin analyzed the data. The first draft of the manuscript was written by Lu Lu, Yi-Xin Jiang, Xiao-Xia Liu, and Jin-Mei Jin. Xin Luan, Li-Jun Zhang, and Ying-Yun Guan designed the experiments and revised this manuscript. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Ethics approval

All animal experiments were obtained by the ethics committee approval of Shanghai University of Traditional Chinese Medicine.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2217024.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No. 82104194, 82173846, and 82274153), Young Talent Lifting Project of China Association of Chinese Medicine [No. CACM-(2021-QNRC2-A08)], Shanghai Rising-Star Program (No. 22QA1409100), 2021 Shanghai Science and Technology Innovation Action Plan (No. 21S11902800), Three-year Action Plan for Shanghai TCM Development and Inheritance Program [ZY(2021-2023)-0401], and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (No. ZYYCXTD-D-202004).