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