RTP4 silencing provokes tumor-intrinsic resistance to immune checkpoint blockade in colorectal cancer
- 02.03.2023
- Original Article—Alimentary Tract
Erschienen in:
- Verfasst von
- Yudai Yamamoto
- Shu Shimada
- Yoshimitsu Akiyama
- Shu Tsukihara
- Raizo Sugimoto
- Ayano Kabashima
- Masanori Tokunaga
- Yusuke Kinugasa
- Yutaka Kawakami
- Shinji Tanaka
- Erschienen in
- Journal of Gastroenterology | Ausgabe 6/2023
Abstract
Background
Recent advances in immune checkpoint blockade (ICB) have improved patient prognosis in mismatch repair-deficient and microsatellite instability-high colorectal cancer (dMMR/MSI-H CRC); however, PD-1 blockade has faced a challenge in early progressive disease. We aimed to understand the early event in ICB resistance using an in vivo model.
Methods
We subcutaneously transplanted the MC38 colon cancer cells into C57BL/6 mice, intraperitoneally injected anti-PD-1 antibody and then isolated ICB-resistant subclones from the recurrent tumors.
Results
Comparative gene expression analysis discovered seven genes significantly downregulated in the ICB-resistant cells. Tumorigenicity assay of the MC38 cells knocked out each of the seven candidate genes into C57BL/6 mice treated with anti-PD-1 antibody and bioinformatics analysis of the relationship between the expression of the seven candidate genes and the outcome of cancer patients receiving immunotherapy identified Rtp4, an interferon-stimulated gene and a chaperon protein of G protein-coupled receptors, as a gene involved in ICB resistance. Immunohistochemical analysis of transplanted tumor tissues demonstrated that anti-PD-1 antibody failed to recruit T lymphocytes in the Rtp4-KO MC38 cells. Mouse and human RTP4 expression could be silenced via histone H3 lysine 9 (H3K9) trimethylation, and public transcriptome data indicated the high expression level of RTP4 in most but not all of dMMR/MSI-H CRC.
Conclusions
We clarified that RTP4 could be silenced by histone H3K9 methylation as the early event of ICB resistance. RTP4 expression could be a promising biomarker for predicting ICB response, and the combination of epigenetic drugs and immune checkpoint inhibitors might exhibit synergistic effects on dMMR/MSI-H CRC.
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- Titel
- RTP4 silencing provokes tumor-intrinsic resistance to immune checkpoint blockade in colorectal cancer
- Verfasst von
-
Yudai Yamamoto
Shu Shimada
Yoshimitsu Akiyama
Shu Tsukihara
Raizo Sugimoto
Ayano Kabashima
Masanori Tokunaga
Yusuke Kinugasa
Yutaka Kawakami
Shinji Tanaka
- Publikationsdatum
- 02.03.2023
- Verlag
- Springer Nature Singapore
- Erschienen in
-
Journal of Gastroenterology / Ausgabe 6/2023
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922 - DOI
- https://doi.org/10.1007/s00535-023-01969-w
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