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Clinical Studies

Mitochondrial DNA copy number plays opposing roles in T-lymphocyte infiltration of colorectal cancer based on mismatch repair status: new directions for immunotherapy?

British Journal of Cancer volume 130, pages 798–807 (2024)Cite this article

Subjects

Abstract

Background

Researchers have previously reported that mitochondrial DNA copy number (mtDNA-CN) can play different roles in microsatellite instable/mismatch repair-deficient (MSI/dMMR) and microsatellite stable/mismatch repair-proficient (MSS/pMMR) colorectal cancer (CRC). To support malignancy, dMMR CRC relies on glycolysis, while pMMR CRC favors oxidative phosphorylation. However, it is unclear whether mtDNA-CN changes are related to T cell infiltration in CRC.

Methods

The mtDNA-CN was detected by qRT-PCR in 532 patients, and the expression of CD3 and CD8 in 485 patients was detected by immunohistochemistry. The correlation between mtDNA-CN and the prognosis of CRC patients was further analyzed, and the correlation between mtDNA-CN and T lymphocyte infiltration was also analyzed. Biopsy specimens from the immune checkpoint inhibitors (ICIs) treatment cohort were obtained to verify the correlation between mtDNA-CN and the efficacy of ICIs. The effects of mtDNA-CN and MMR status on gene expression were analyzed by RNA-seq.

Results

Our results show that mtDNA-CN has inverse relationships to CRC prognosis in cases with different MMR statuses, potentially inducing the U-shaped association in CRC. The opposing correlations between mtDNA-CN and T lymphocyte infiltration in cases of dMMR CRC and pMMR CRC further suggest that mtDNA-CN might play an important role in CRC development. More importantly, cases of pMMR CRC with lower mtDNA-CN and of dMMR CRC with higher mtDNA-CN can benefit more dramatically from ICIs. Furthermore, RNA-seq revealed a link between the level of mtDNA-CN and T lymphocyte infiltration in CRC cases with different MMR statuses.

Conclusion

Our study found a potential relationship between mtDNA-CN and CRC development that differs by MMR status, potentially providing a rationale for the use of mtDNA-CN as both a predictive biomarker and a therapeutic target for ICIs.

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Fig. 1: Distribution characteristics of mtDNA-CN in CRC.
Fig. 2: Correlation between mtDNA-CN and CRC prognosis.
Fig. 3: Correlation between mtDNA-CN and T-lymphocyte infiltration in CRC.
Fig. 4: Clinical verification of the correlation between mtDNA-CN and ICI treatment efficacy.
Fig. 5: Identification and functional analysis of DEGs.

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Data availability

The data from RNA-seq array in this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This study was supported by National Key Clinical Discipline.

Funding

The programme of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Science and technology key research and development plan project of Guangzhou (China) (202103000072), Natural Science Foundation of Guangdong Province (China) (2018A030313621), Science and Technology Projects in Guangzhou (202206010062), Sun Yat-sen University Clinical Research 5010 Programme (2016005), Shenzhen “San Ming Projects” Research (Grant No.lc202002).

Author information

Author notes

  1. These authors contributed equally: Mian Chen, Huashan Liu, Wenfeng Liang.

Authors and Affiliations

  1. Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Mian Chen, Huashan Liu, Wenfeng Liang, Pinzhu Huang, Fujin Ye, Yebing Cai, Zhenxing Liang, Li Xiong, Liang Kang & Liang Huang

  2. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, Hubei, China

    Mian Chen

  3. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Mian Chen, Huashan Liu, Wenfeng Liang, Pinzhu Huang, Fujin Ye, Yebing Cai, Zhenxing Liang, Li Xiong, Liang Kang & Liang Huang

  4. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Mian Chen, Huashan Liu, Wenfeng Liang, Pinzhu Huang, Fujin Ye, Yebing Cai, Zhenxing Liang, Li Xiong, Liang Kang & Liang Huang

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Contributions

LH and LK contributed to the conception of the study and supervision. MC, HSL and WFL contributed to experiment, data collection, quality assessment and manuscript draft. PZH and FJY contributed to statistical analysis and interpretation of data. YBC, ZXL and LX contributed to the interpretation of data and revision of the manuscript draft. All authors have approved the final draft of the manuscript.

Corresponding authors

Correspondence to Liang Kang or Liang Huang.

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The authors declare no competing interests.

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All human tissue samples were obtained by the Sixth Affiliated Hospital of Sun Yat-sen University and collected with written informed consent from donors. In addition, all procedures were conducted with the permission of the Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University (Project number: E2021156).

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Chen, M., Liu, H., Liang, W. et al. Mitochondrial DNA copy number plays opposing roles in T-lymphocyte infiltration of colorectal cancer based on mismatch repair status: new directions for immunotherapy?. Br J Cancer 130, 798–807 (2024). https://doi.org/10.1038/s41416-023-02568-5

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