Cancer is a dark mirror to the normal processes of tissue maintenance, in which normally helpful processes run amok and become pathological when harnessed to make tumors grow. A cancer is a subversion of normal regeneration and maintenance. Aging, on the other hand, is a progressive disruptive failure of those same mechanisms of regeneration and maintenance. Thus many of the issues found in aging are also of interest to the cancer research community, and have been studied in that context for considerably longer than the modern longevity biotechnology community has existed. It is quite common to find that an existing class of drug that might be of interest in the context of aging was initially developed as a cancer therapy.
T cell exhaustion is a feature of aging. These adaptive immune cells become unresponsive and do not contribute to immune defense as they should. T cell exhaustion is also a well known feature of cancer, one of the ways in which the immune system falls short in its ability to destroy a growing tumor. T cell exhaustion also hinders the deployment of immunotherapies that depend on the immune system's anti-cancer capabilities. Immune cells engineered to attack a cancer and introduced into the patient as a therapy often burn out and become exhausted long before they can make a meaningful dent in the size of a tumor, a faster and more exaggerated version of what happens to native, unmodified immune cells.
Today's research materials discuss what happens under the hood in the exhaustion of T cells, and point to a regulator that can adjust the balance of activity versus exhaustion. Exhaustion of T cells is a metabolic collapse, the T cell has exhausted its supply of energy by conducting the energetically expensive process of making cytotoxic proteins to kill cancerous cells. The pace at which this weapons manufacture progresses determines whether the T cell can sustain its activity over time, or whether it will quickly become exhausted. Some cancers can be overcome by a short period of aggressive attacks by highly active T cells, but in other cases that is not enough, a longer period of lower intensity anti-cancer activity would produce better results.
New Strategy Could Prevent T Cell Exhaustion and Boost Immunotherapy
A major pillar of cancer immunotherapy involves stimulating T cells, the specialized killers of the immune system, to attack tumors. But this strategy has been undermined by the tendency of T cells to tire out before finishing the job. When the cells reach the fatigued stage - called T cell exhaustion - these immune cells lose the ability to sustain the attack and keep cancer growth under control. T cells enter the exhausted state to save themselves. They stop fighting to avoid becoming overstimulated and dying. When a T cell is in attack mode and making cytotoxic proteins, the mitochondria must convert nutrients from food into adenosine triphosphate (ATP). ATP is the primary molecule used by all living cells to store and transfer energy.
Researchers have now identified a signaling molecule called MEK that plays a key role in T cell exhaustion. "Think of ATP as the currency in a fund that the cell spends down. If you spend ATP on one thing, you don't have enough to do something else. The exhaustion program is a sign that the cell's bank account is getting close to zero. MEK tells exhausted cells whether to conserve fuel or go for broke. What we found is that inhibiting MEK makes the cells more conservative - helping them live longer while reducing the rate at which they produce the proteins that actually kill cancer cells." So MEK is both the problem and part of the solution - it keeps T cells at full power but risks complete burnout. This means blocking MEK is a double-edged sword: It weakens the attack but keeps the soldiers alive.
MEK inhibitors could be used selectively to rev up T cells. Patients with large tumors or a small number of immune cells are unlikely to have a strong enough response to immunotherapy to finish off the tumor quickly. In those cases, a MEK inhibitor-induced slow burn - even in an exhausted state - allows T cells to persist, which is essential when when either the task at hand (the tumor) is large or the workforce (the number of T cells) is small.
MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion
Loss of mitochondrial function promotes CD8+ T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion.
Mechanistically, chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.
View the full article at FightAging
