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.

References:

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.