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Translational Therapeutics

Low-dose arsenic trioxide inhibits pancreatic stellate cell activation via LOXL3 expression to enhance immunotherapy in pancreatic cancer

British Journal of Cancer volume 131, pages 1928–1941 (2024)Cite this article

Subjects

Abstract

Background

Pancreatic cancer (PC) is characterized by abnormally fibrotic mesenchyme, which notably influences on the effectiveness of immunotherapy. Low-dose arsenic trioxide (ATO, 1.0 μM) can inhibit the activation of pancreatic stellate cells (PSCs) and affect fibrosis, which is a potential strategy for enhancing the sensitivity to immunotherapy.

Methods

Extracellular matrix (ECM) models were employed to assess the regulatory effects of ATO on ECM and peripheral blood mononuclear cells. Orthotopic C57BL/6J models were utilized to evaluate the influence of ATO on CD8+T cell infiltration and immunotherapy in PC. Additionally, nanomaterials loaded with ATO designed to specifically target PSCs (scAbFAP-α-HMSNs-PAA-ATO) were produced to enhance targeting effects of ATO.

Results

Low-dose ATO (1.0 μM) suppressed PSCs activation, exhibiting potential for synergistic immunotherapy. Under low-dose ATO intervention, ECM underwent remodeling, leading to increases in CD8+T cell infiltration, thereby enhancing anti-PD-L1 therapy effect. We further demonstrated that low-dose ATO remodeled ECM by regulating the expression of LOXL3 in PSCs. scAbFAP-α-HMSNs-PAA-ATO exhibited improved targeting capabilities, and enhanced capacity to inhibit fibrosis and sensitize immunotherapy.

Conclusions

Our research reveals that low-dose ATO, by regulating LOXL3, remodels the ECM and enhances CD8+T cell infiltration, thus sensitizing the efficacy of immunotherapy, which provides a novel strategy for comprehensive treatment to PC.

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Fig. 1: Low-dose ATO inhibits fibrosis and promotes the infiltration of CD8+ T cells.
Fig. 2: Low-dose ATO inhibits PSCs activation and enhances PBMCs killing effects.
Fig. 3: Low-dose ATO enhances the effect of immunotherapy in PC.
Fig. 4: LOXL3 mediates PSCs activation and fibrosis in PC.
Fig. 5: LOXL3 mediates fibrosis and tumor immunosuppression in PC.
Fig. 6: scAb-NPs-ATO inhibit PSCs activation in vitro more efficiently.
Fig. 7: scAb-NPs-ATO sensitizes PC to anti-PD-L1 immunotherapy.
Fig. 8: Proposed model of low-dose ATO inhibiting fibrosis and sensitizing immunotherapy for pancreatic cancer.

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Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was jointly supported by the National Natural Science Foundation of China (82203036, 81874057, 82373025, 82003175), Guangzhou Science and Technology Plan Project (SL2024A04J01991), China Postdoctoral Science Foundation (2023M734051), Medical Scientific Research Foundation of Guangdong Province of China (A2016210), Science and Technology Program of Guangzhou, China (202102020161), Guangdong Basic and Applied Basic Research Foundation (2024A1515012799, 2021A1515110240).

Author information

Author notes

  1. These authors contributed equally: Yue Zhao, Yunlong Li, Jinmao Zou.

Authors and Affiliations

  1. Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Yue Zhao, Yunlong Li, Jinmao Zou, Tairan Guo, Ziyi Zhong, Yaqing Li, Shaojie Chen, Kaihong Huang, Guoda Lian & Yuzhou Huang

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Yue Zhao, Yunlong Li, Jinmao Zou, Tairan Guo, Ziyi Zhong, Yaqing Li, Shaojie Chen, Jiajia Li, Kaihong Huang, Guoda Lian & Yuzhou Huang

  3. VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, China

    Yue Zhao

  4. Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Jiajia Li

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Contributions

YZ, YL, and JZ contributed equally to this work. YH, GL, KH, and JL developed the concept and supervised the experiments. YH wrote the original draft. YH, JL, GL, KH, YZ, YL, and JZ wrote the manuscript. YZ, YL, JZ, ZZ, TG, and SC carried out the experiments and performed the statistical analyses. YZ and YL performed the data analysis. YL, ZZ, and TG provided the materials.

Corresponding authors

Correspondence to Jiajia Li, Kaihong Huang, Guoda Lian or Yuzhou Huang.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The use of human samples was approved by Sun Yat-sen Memorial Hospital Ethics Committee and the informed consent from all participants were obtained (SYSKY-2023-116-01). All methods involved in this study were carried out in accordance with relevant guidelines and regulations. All animals care and experimental procedures were conducted according to the National Research Council’s Guidelines for the Care and Use of Laboratory Animals, and were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University Cancer Center (L102012022040E).

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Zhao, Y., Li, Y., Zou, J. et al. Low-dose arsenic trioxide inhibits pancreatic stellate cell activation via LOXL3 expression to enhance immunotherapy in pancreatic cancer. Br J Cancer 131, 1928–1941 (2024). https://doi.org/10.1038/s41416-024-02880-8

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