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Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers

Background Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. Methods We reanalyzed public whole-exome...

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Published in:British journal of cancer 2023-10, Vol.129 (7), p.1105-1118
Main Authors: Kobayashi, Yuta, Niida, Atsushi, Nagayama, Satoshi, Saeki, Koichi, Haeno, Hiroshi, Takahashi, Kazuki K., Hayashi, Shuto, Ozato, Yuki, Saito, Hideyuki, Hasegawa, Takanori, Nakamura, Hiromi, Tobo, Taro, Kitagawa, Akihiro, Sato, Kuniaki, Shimizu, Dai, Hirata, Hidenari, Hisamatsu, Yuichi, Toshima, Takeo, Yonemura, Yusuke, Masuda, Takaaki, Mizuno, Shinichi, Kawazu, Masahito, Kohsaka, Shinji, Ueno, Toshihide, Mano, Hiroyuki, Ishihara, Soichiro, Uemura, Mamoru, Mori, Masaki, Doki, Yuichiro, Eguchi, Hidetoshi, Oshima, Masanobu, Suzuki, Yutaka, Shibata, Tatsuhiro, Mimori, Koshi
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Language:English
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Summary:Background Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. Methods We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. Results Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. Conclusions Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.
ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-023-02395-8