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

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

The development of immune checkpoint inhibitors (ICIs) has produced unprecedented clinical outcomes for patients with microsatellite instable/mismatch repair-deficient (MSI/dMMR) CRC. Unfortunately, the vast majority of patients with microsatellite stable/mismatch repair-proficient (MSS/pMMR) CRC do not benefit from immunotherapy due to poor T cell infiltration [1]. Therefore, it is important to gain a better understanding of the regulatory mechanisms underlying cytotoxic T cell infiltration.

Mitochondria are critical metabolic organelles involved in metabolism alterations and cellular functions. Increasing evidence has demonstrated that altered metabolism affects TME reprogramming [2]. Changes in mitochondrial DNA copy number (mtDNA-CN) reflect mitochondrial biogenesis and function, serving as a substitute index of mitochondrial activity [3]. Previous studies have demonstrated that mtDNA-CN is much lower in MSI CRC than in MSS CRC [4]. The regulation of transcription factor A truncating mutations leads to mtDNA-CN changes and mitochondrial instability, distinguishing most cases of dMMR CRC from pMMR CRC [5]. Consequently, the occurrence and development of CRC are likely affected by mtDNA-CN changes. However, the relationship between mtDNA-CN and T lymphocyte infiltration in CRC is still unclear. It is important to clarify the potential regulatory mechanisms behind cytotoxic T lymphocyte infiltration in order to develop effective strategies for tumor immunotherapy. 

Interestingly, 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.

In short, 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. It is undeniable that the specimens for clinical validation of this study are limited. Therefore, these findings need to be verified in a larger cohort in the future. And further prospective recruitment research samples were evaluated.


1.Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020;20(11):662-80; doi: 10.1038/s41568-020-0285-7.

2.Siska PJ, Beckermann KE, Mason FM, Andrejeva G, Greenplate AR, Sendor AB, et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. 2017;2(12); doi: 10.1172/jci.insight.93411.

3.Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345(6204):1250684; doi: 10.1126/science.1250684.

4.van Osch FH, Voets AM, Schouten LJ, Gottschalk RW, Simons CC, van Engeland M, et al. Mitochondrial DNA copy number in colorectal cancer: between tissue comparisons, clinicopathological characteristics and survival. Carcinogenesis. 2015;36(12):1502-10; doi: 10.1093/carcin/bgv151.

5.Guo J, Zheng L, Liu W, Wang X, Wang Z, Wang Z, et al. Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer. Cancer Res. 2011;71(8):2978-87; doi: 10.1158/0008-5472.Can-10-3482.

Please sign in or register for FREE

If you are a registered user on Research Communities by Springer Nature, please sign in

Subscribe to the Topic

Colorectal Cancer
Life Sciences > Biological Sciences > Cancer Biology > Cancers > Gastrointestinal Cancer > Colorectal Cancer

Related Collections

With collections, you can get published faster and increase your visibility.

Digital Imaging

BJC’s Digital Imaging series is open to receiving submissions assessing:
  • State-of-the-art in digital imaging technology and computational output;
  • Radiomics;
  • Algorithms and approaches designed to predict therapeutic response and enable “personalized medicine”;
  • Interrogation of the immune microenvironment and implications for immunotherapy selection;
  • Challenges of implementation in clinical practice;
  • Controversial applications of digital imaging

Publishing Model: Hybrid

Deadline: Ongoing