The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression
© 2021. The Author(s)..
PURPOSE: A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis.
PATIENTS AND METHODS: We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA.
RESULTS: Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation.
CONCLUSION: Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient's constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico - 24(2022), 6 vom: 27. Juni, Seite 1157-1167 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bousquet, P A [VerfasserIn] |
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| Links: |
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| Themen: |
CD4 |
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| Anmerkungen: |
Date Completed 17.05.2022 Date Revised 16.09.2023 published: Print-Electronic ClinicalTrials.gov: NCT01816607 Citation Status MEDLINE |
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| doi: |
10.1007/s12094-021-02756-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Bousquet, P A |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression |
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| 500 | |a Date Revised 16.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT01816607 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. The Author(s). | ||
| 520 | |a PURPOSE: A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis | ||
| 520 | |a PATIENTS AND METHODS: We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA | ||
| 520 | |a RESULTS: Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation | ||
| 520 | |a CONCLUSION: Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient's constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility | ||
| 520 | |a TRIAL REGISTRATION: ClinicalTrials.gov NCT01816607; registration date: 22 March 2013 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CD4 | |
| 650 | 4 | |a Colorectal cancer | |
| 650 | 4 | |a Immune cells | |
| 650 | 4 | |a Metastasis | |
| 650 | 4 | |a Mitochondrial DNA | |
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| 700 | 1 | |a Fuglestad, A J |e verfasserin |4 aut | |
| 700 | 1 | |a Lüders, T |e verfasserin |4 aut | |
| 700 | 1 | |a Esbensen, Y |e verfasserin |4 aut | |
| 700 | 1 | |a Juul, H V |e verfasserin |4 aut | |
| 700 | 1 | |a Johansen, C |e verfasserin |4 aut | |
| 700 | 1 | |a Lyckander, L G |e verfasserin |4 aut | |
| 700 | 1 | |a Bjørnetrø, T |e verfasserin |4 aut | |
| 700 | 1 | |a Inderberg, E M |e verfasserin |4 aut | |
| 700 | 1 | |a Kersten, C |e verfasserin |4 aut | |
| 700 | 1 | |a Redalen, K R |e verfasserin |4 aut | |
| 700 | 1 | |a Ree, A H |e verfasserin |4 aut | |
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