A widely available nutritional supplement—nicotinamide riboside (NR)—may energize tumor-infiltrating T lymphocytes (TILs) exhausted by their struggles against the tumor microenvironment. Specifically, NR may recharge TILs by improving mitochondrial fitness and stimulating mitophagy, the elimination of damaged mitochondria.

In terminally exhausted TILs, the damage typically suffered by mitochondria is depolarization. That is, the mitochondria lose the voltage they need to generate energy. They pile up like so many dead batteries.

The potential advantage of NR-stimulated mitochondria was recognized by researchers led by Ping-Chih Ho, PhD, at the Lausanne Branch of the Ludwig Institute for Cancer Research. These researchers began experimenting with NR, a vitamin B3 variant that has been shown to improve mitochondrial fitness in various cell types, after they noticed that in TILs, there is an association between T-cell exhaustion and large numbers of depolarized mitochondria.

Details of this work appeared October 5 in the journal Nature Immunology, in an article titled, “Disturbed mitochondrial dynamics in CD8+ TILs reinforce T-cell exhaustion.” The article describes a mechanism to explain how the accumulation of depolarized mitochondria is caused by decreased mitophagy activity. The mechanism is driven by stressors in the tumor microenvironment, and it not only instigates exhaustion, it also leads to terminal exhaustion, a state that reflects epigenetic reprogramming.

“Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T-cell receptor stimulation, microenvironmental stressors, and PD-1 signaling,” the article’s authors wrote. “Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T-cell exhaustion.”

By carrying out functional, transcriptomic, and epigenetic analyses, the researchers revealed that when TILs accumulate depolarized mitochondria as a result of decreased mitophagy, they exemplify terminal exhaustion.

“TILs often have a high affinity for antigens expressed by cancer cells,” said Ho. “This means that, in principle, they should attack cancer cells vigorously. But we often don’t see that.

“People have always wondered why because it suggests that the best soldiers of the immune system are vulnerable when they enter the battlefield of the tumor. Our study provides a mechanistic understanding of why this happens and suggests a possible strategy for preventing the effect that can be quickly evaluated in clinical trials.”

The inner recesses of tumors are often starved of oxygen and essential nutrients, such as the sugar glucose. Cells in these stressful conditions adjust their metabolic processes to compensate—for example, by making more mitochondria and burning their fat reserves for energy.

In tumors, prolonged stimulation by cancer antigens is known to push TILs into an exhausted state marked by the expression of PD-1—a signaling protein that suppresses T-cell responses and is targeted by existing “checkpoint blockade” immunotherapies. If sustained, such exhaustion can become permanent, persisting even when the stimulus of cancer antigens is removed.

Ho and colleagues have shown that the accumulation of depolarized mitochondria is caused primarily by the TIL’s inability to remove and digest damaged ones through mitophagy. “The TILs can still make new mitochondria but, because they don’t remove the old ones, they lack the space to accommodate the new ones,” said Ho.

The genomes of these TILs are also reprogrammed by epigenetic modifications—chemical groups added to DNA and its protein packaging—to induce patterns of gene expression associated with terminal exhaustion.

The researchers found that the breakdown in mitophagy stems from a convergence of factors: chronic stimulation by cancer antigens, PD-1 signaling, and the metabolic stress of nutrient and oxygen deprivation. They also show that the epigenetic reprogramming that fixes TILs in a terminally exhausted state is a consequence, not a cause, of the mitochondrial dysfunction.

Related work done by other researchers—including co-authors in the current study, Ludwig Lausanne investigator Nicola Vannini, PhD, and Ludwig Lausanne director George Coukos, PhD—had shown that NR can boost mitophagy and improve mitochondrial fitness in a variety of other cell types. Mindful of these findings, the researchers in the current study explored whether NR might also prevent TILs from committing to terminal exhaustion.

Ho and colleagues conducted cell culture experiments showing that the supplement improved the mitochondrial fitness and function of T cells grown under stressors resembling those of the tumor microenvironment. “Supplementation with NR,” they reported, “enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment.”

Dietary supplementation with NR stimulated the antitumor activity of TILs in a mouse model of skin cancer and colon cancer. When combined with anti-PD-1 and another type of checkpoint blockade, anti-CTLA-4 immunotherapy, it significantly inhibited the growth of tumors in the mice.

“We have shown that we may be able to use a nutritional approach to improve checkpoint blockade immunotherapy for cancer,” said Ho.

Ho and his colleagues are now exploring the signals from depolarized mitochondria that epigenetically reprogram TILs for terminal exhaustion—information that could be more generally applied to improve cancer immunotherapy.

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