loading page

The mitochondrial DNA constitution shaping T cell immunity in patients with rectal cancer at high risk of metastatic progression
  • +10
  • Paula Bousquet,
  • Sebastian Meltzer,
  • Anniken Fuglestad,
  • Torben Lüders,
  • Ying Esbensen,
  • Hedvig Juul,
  • Christin Johansen,
  • Lars Gustav Lyckander,
  • Tonje Bjørnetrø,
  • Else Marit Inderberg,
  • Christian Kersten,
  • Kathrine Redalen,
  • Anne Ree
Paula Bousquet
Akershus University Hospital

Corresponding Author:[email protected]

Author Profile
Sebastian Meltzer
Akershus University Hospital
Author Profile
Anniken Fuglestad
Akershus University Hospital
Author Profile
Torben Lüders
Akershus University Hospital
Author Profile
Ying Esbensen
Akershus University Hospital
Author Profile
Hedvig Juul
Oslo University Hospital
Author Profile
Christin Johansen
Akershus University Hospital
Author Profile
Lars Gustav Lyckander
Akershus University Hospital
Author Profile
Tonje Bjørnetrø
Akershus University Hospital
Author Profile
Else Marit Inderberg
Oslo University Hospital
Author Profile
Christian Kersten
Sørlandet Sykehus HF
Author Profile
Kathrine Redalen
Norwegian University of Science and Technology
Author Profile
Anne Ree
Akershus University Hospital
Author Profile

Abstract

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. 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. A high mtDNA variant number, coexisting with an mtDNA non-H haplogroup, was 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 and natural killer T cells and, of note, the naïve (LAG-3+) helper T cell population, all inversely correlated with cell-free damaged mtDNA in serum known to cause antagonising inflammation. The statistical associations suggested that patient’s constitutional mtDNA manifests the helper T cell capacity to mount immunity that controls metastatic susceptibility.
Jun 2022Published in Clinical and Translational Oncology volume 24 issue 6 on pages 1157-1167. 10.1007/s12094-021-02756-w