In a new study, researchers have found a mechanism by which the tumor’s harsh internal environment sabotages T lymphocytes, leading cellular agents of the anticancer immune response.
They found how a variety of stressors prevalent in the tumor microenvironment disrupt the power generators, or mitochondria, of tumor-infiltrating T lymphocytes (TILs).
They also found that a widely available nutritional supplement, nicotinamide riboside (NR), a chemical analogue of vitamin B3, helps TILs overcome the mitochondrial dysfunction and preserves their ability to attack tumors in melanoma and colon cancer.
The research was conducted by a team at Ludwig Cancer Research.
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.
In the study, the team found that exhausted TILs are packed with damaged—or ‘depolarized’—mitochondria.
Like old batteries, depolarized mitochondria essentially lack the voltage the organelles require to generate energy.
The team found 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 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 showed that NR, a chemical analog of vitamin B3, can boost mitophagy and improve mitochondrial fitness in a variety of other cell types.
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.
More notably, dietary supplementation with NR stimulated the anti-tumor 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.
The findings showed that there may be a nutritional approach to improve checkpoint blockade immunotherapy for cancer.
One author of the study is Ludwig Lausanne Associate Member Ping-Chih Ho.
The study is published in Nature Immunology.
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