Nutritional Supplement Nicotinamide Riboside Might Boost Cancer Immunotherapy

Researchers have uncovered a mechanism by which tumor's harsh internal environment sabotages T lymphocytes, leading cellular agents of the anticancer immune response. Reported in Nature Immunology, the study describes how a variety of stressors prevalent in the tumor microenvironment disrupt the mitochondria of tumor-infiltrating T lymphocytes (TILs), pushing them into terminal exhaustion.

The study, led by a team at the Ludwig Institute for Cancer Research, also found that the widely available nutritional supplement nicotinamide riboside (NR)-helps TILs overcome the mitochondrial dysfunction and preserves their ability to attack tumors in mouse models of melanoma and colon cancer.

"Our functional analysis revealed that those T cells with the most depolarized mitochondria behaved most like terminally exhausted T cells," said study leader Ping-Chih Ho. Ho and colleagues show that the accumulation of depolarized mitochondria is caused primarily by the TIL's inability to remove and digest damaged ones through a process known as 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 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.

With this in mind, the researchers explored whether NR might also prevent TILs from committing to terminal exhaustion. Their cell culture experiments showed that the supplement improved the mitochondrial fitness and function of T cells grown under stressors resembling those of the tumor microenvironment. 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.