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Clinical Studies

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

British Journal of Cancer volume 129, pages 1105–1118 (2023)Cite this article

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Abstract

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.

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Fig. 1: Identification of driver genes in MSI-H CRCs.
Fig. 2: HLA mutations and loss of heterozygosity (LOH) cause loss of antigen-presentation function.
Fig. 3: Mutation profiles and evolutionary trees of MSI-H CRCs.
Fig. 4: Multiregion immunohistochemistry (IHC) demonstrated the intratumor heterogeneity of the immune microenvironment.
Fig. 5: Darwinian selection mainly shapes ITH in MSI-H CRCs.
Fig. 6: Simulation model demonstrated Darwinian selection shapes ITH under the high immune selective pressure.

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Data availability

Raw sequencing data were deposited in the Japanese Genotype-phenotype Archive under the accession number JGAS000322.

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Acknowledgements

We thank the members of the Institute for Department of Surgery of Kyushu University Beppu Hospital for sample collection and analysis. We also thank K. Oda, M. Kasagi, S. Sakuma, N. Mishima, T. Kawano, M. Oshiumi, and M. Utou for their technical assistance.

Funding

This project was supported by Science (JSPS) Grant-in-Aid for Science Research (15H05912, 19K09220, 22H04925:PAGS, 20H05039, 20K08930, 20K17556, 21K07179, 22K02903, 22K09006, 23K06765, and 23K08074), Priority Issue on Post-K computer (hp170227, hp160219), OITA Cancer Research Foundation (JP20cm0106475h0001), the Project for Cancer Research and Therapeutic Evolution (19 cm0106504h0004, 21 cm0106475h0002), AMED under Grant Number (23ck0106825h001, 23ck0106800h001, 22ama221501h0001, 21ck0106690s0201, 20ck0106547h0001, 20ck0106541h0001 and 22ama221XXXh0001), a research grant from the Takeda Science Foundation, and The Princess Takamatsu Cancer Research Fund. This study used the supercomputing resources provided by the Human Genome Center, Institute of Medical Science, University of Tokyo (http://sc.hgc.jp/shirokane.html).

Author information

Authors and Affiliations

  1. Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, 874-0838, Japan

    Yuta Kobayashi, Yuki Ozato, Hideyuki Saito, Akihiro Kitagawa, Kuniaki Sato, Dai Shimizu, Hidenari Hirata, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda & Koshi Mimori

  2. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka, 565-0871, Japan

    Yuta Kobayashi, Yuki Ozato, Akihiro Kitagawa, Mamoru Uemura, Yuichiro Doki & Hidetoshi Eguchi

  3. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1, Sirokane-dai, Minato-Ku, Tokyo, 108-8639, Japan

    Atsushi Niida, Kazuki K. Takahashi & Tatsuhiro Shibata

  4. Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan

    Satoshi Nagayama

  5. Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, 611-0041, Japan

    Satoshi Nagayama

  6. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, 227-8561, Japan

    Koichi Saeki

  7. Division of Integrated Research, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda City, Chiba, 278-0022, Japan

    Hiroshi Haeno

  8. Division of Systems Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Shuto Hayashi

  9. Division of Health Medical Data Science, Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan

    Takanori Hasegawa

  10. Division of Cancer Genomics, National Cancer Center Japan, Research Institute 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hiromi Nakamura & Tatsuhiro Shibata

  11. Department of Pathology, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, 874-0838, Japan

    Taro Tobo

  12. Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, 811-1395, Japan

    Kuniaki Sato

  13. Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan

    Dai Shimizu

  14. Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Hidenari Hirata

  15. Division of Cancer Research, Center for Advanced Medical Innovation, Kyushu University, Fukuoka, 812-8582, Japan

    Shinichi Mizuno

  16. Division of Cellular Signaling, National Cancer Center Japan, Research Institute 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Masahito Kawazu, Shinji Kohsaka, Toshihide Ueno & Hiroyuki Mano

  17. Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Soichiro Ishihara

  18. Faculty of Medicine, Tokai University, Isegahara, 259-1193, Japan

    Masaki Mori

  19. Division of Genetics, Cancer Research Institute, Kanazawa University, Kadoma-Cho, Kanazawa, 920-1164, Japan

    Masanobu Oshima

  20. Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan

    Yutaka Suzuki

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Contributions

YK: Study design, sample collection, sample preparation, data analysis, and manuscript writing. AN, KSaeki, KT and HHaeno: Study design, project management, data analysis, and manuscript writing. SN: Study design, project management, sample collection, and sample preparation. TTobo: Histopathological diagnosis. SH, YO, HS, TH, and HN: Data analysis. AK, KSato, DS, HHirata, YH, TToshima, YY, TM, MO, SM, MU, MM, YD, and HE: Study design. TU, HM, and SI: Sample collection. YS: Sequence data assembly and study design. TS and KM: Project supervision, study design, and final approval of the article.

Corresponding author

Correspondence to Koshi Mimori.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study design was approved by the institutional review boards and ethics committees of hospitals where the study participants were admitted (Cancer Institute Hospital, Japanese Foundation for Cancer Research Institutional Review Board: Protocol Number 2011-1075, Kyushu University Institutional Review Board: Protocol Number 2020-74). The study was conducted in accordance with the principles of the Declaration of Helsinki. All patients provided informed consent.

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Consent was obtained from all participants to publish supporting data including Supplementary Table 1.

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Kobayashi, Y., Niida, A., Nagayama, S. et al. Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers. Br J Cancer 129, 1105–1118 (2023). https://doi.org/10.1038/s41416-023-02395-8

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  • DOI: https://doi.org/10.1038/s41416-023-02395-8

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