There remains a great deal yet to be learned of the fine details of cellular biochemistry and the interactions between cells and their environments. Even just one cell remains a fantastically complex, incompletely understood collection of mechanisms. As a general rule, given further study, any aspect of cellular biology will turn out to be more complex than the present understanding suggests it to be. This is one of the reasons to advocate for approaches to aging that try to repair known forms of cell and tissue damage rather than adjust cell behavior. To use an analogy, it is a lot easier to periodically remove rust than it is to build and experimentally validate a computational model of how rust progresses to structural failure in a complex arrangement of pipes, and then use the model to test ways to alter the biochemistry of rust or the form of the structure in order to slow the corrosion.
So to today's example of newly understood complexity in cellular biochemistry. It hasn't been all that long since researchers established that cells are capable of using mitochondria as signals, secreting them and taking them up, or exchanging them via short-lived nanotubes established between cells for this purpose. Any mechanism employed by normal cells is on the table for exploitation by cancerous cells, and this is the case for transport of mitochondria. It turns out that tumor cells will feed dysfunctional mitochondria to nearby immune cells, suppressing their normal tendency to attack the cancerous cells. Numerous other immunosuppression techniques are employed by cancer cells; in principle, finding ways to disable any one of them might give some advantage to cancer patients.
Immune evasion through mitochondrial transfer in the tumour microenvironment
Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs.
Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo.
Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
View the full article at FightAging
