The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression

• P. A. Bousquet ^[1] ; S. Meltzer ^[1] ; A. J. Fuglestad ^[4] ; T. Lüders ^[5] ; Y. Esbensen ^[5] ; H. V. Juul ^[2] ; C. Johansen ^[1] ; L. G. Lyckander ^[1] ; T. Bjørnetrø ^[1] ; E. M. Inderberg ^[2] ; C. Kersten ^[6] ; K. R. Redalen ^[3] ; A. H. Ree ^[7]
  1. [1] Akershus University Hospital

     Akershus University Hospital

     Noruega

     
  2. [2] Oslo University Hospital

     Oslo University Hospital

     Noruega

     
  3. [3] Norwegian University of Science and Technology

     Norwegian University of Science and Technology

     Noruega

     
  4. [4] Department of Oncology, Akershus University Hospital, Lorenskog, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway Centre for Cancer Treatment, Sørlandet Hospital, Kristiansand, Norway
  5. [5] Department of Clinical Molecular Biology, Akershus University Hospital, Lorenskog, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  6. [6] Centre for Cancer Treatment, Sørlandet Hospital, Kristiansand, Norway Department of Oncology, Akershus University Hospital, Lorenskog, Norway
  7. [7] Department of Oncology, Akershus University Hospital, Lorenskog, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway

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• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 24, Nº. 6 (junio), 2022, págs. 1157-1167
• Idioma: inglés
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• Resumen

  • 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.