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Tumor stroma-derived ANGPTL2 potentiates immune checkpoint inhibitor efficacy

Cancer Gene Therapy (2024)Cite this article

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Abstract

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic. We recently reported that tumor stroma-derived angiopoietin-like protein 2 (ANGPTL2) has tumor suppressive activity by enhancing dendritic cell-mediated CD8+ T cell anti-tumor immune responses. However, a direct impact of ANGPTL2 on ICI anti-tumor effect remains unclear. Here, we use a murine syngeneic model to show that host ANGPTL2 facilitates CD8+ T cell cross-priming and contributes to anti-tumor responses to ICIs in this context. Importantly, our analysis of public datasets indicated that ANGPTL2 expression is associated with positive responses to ICI therapy by human melanoma patients. We conclude that ANGPTL2-mediated stromal cell crosstalk facilitates anti-tumor immunity and ICI responsiveness. These findings overall provide novel insight into ANGPTL2 anti-tumor function and regulation of ICI-induced anti-tumor immunity.

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Fig. 1: Host ANGPTL2 deficiency attenuates ICI anti-tumor effect.
Fig. 2: Host ANGPTL2 deficiency decreases anti-tumor immune responses during ICI treatment.
Fig. 3: ICI anti-tumor effect in Angptl2−/− mice is rescued by dendritic cell vaccination.
Fig. 4: PDGFRα+ stromal cells in the tumor microenvironment express ANGPTL2 during ICI treatment.
Fig. 5: Correlation of ANGPTL2 expression with responses to ICI in human melanoma patients.
Fig. 6: Model proposing regulation of ICI anti-tumor effects by stromal ANGPTL2 signaling.

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All data are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Kiyoka Tabu, Noriko Shirai, and Sayomi Iwaki for technical assistance. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (grant 23K06638 to HH, grant 21K07101 to TK), the Takeda Science Foundation (HH), a Tasaki Memorial Research Grant for 2022 (HH), a grant from the Center for Metabolic Regulation of Healthy Aging (CMHA) (HH), and the Kato Memorial Bioscience Foundation (TK).

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Authors and Affiliations

  1. Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Haruki Horiguchi, Tsuyoshi Kadomatsu, Tomoya Yamashita, Shinsei Yumoto, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata & Yuichi Oike

  2. Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Haruki Horiguchi & Yuichi Oike

  3. Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Tsuyoshi Kadomatsu, Kazutoyo Terada, Toshiro Moroishi & Yuichi Oike

  4. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Shinsei Yumoto & Taichi Horino

  5. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Yuki Ichigozaki, Toshihiro Kimura & Satoshi Fukushima

  6. Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Toshiro Moroishi

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Contributions

HH designed the study, performed and analyzed experiments, and wrote the paper. TK designed and supervised the study. TY, SY, TH, and MS performed and analyzed experiments. KT provided recombinant ANGPTL2 protein. KM provided Angptl2 mutant mice. YI, TK, and SF collected human samples. TM supervised the study. YO coordinated, designed, and supervised the study and wrote the paper. All authors discussed the data and commented on the paper.

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Correspondence to Haruki Horiguchi or Yuichi Oike.

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Horiguchi, H., Kadomatsu, T., Yamashita, T. et al. Tumor stroma-derived ANGPTL2 potentiates immune checkpoint inhibitor efficacy. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00757-9

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