The body’s immune response to cancer comes, in part, from a type of white blood cell called T lymphocytes. Depletion of nutrients, a metabolic challenge, from the cellular environments that tumors create set up challenges for T lymphocyte antitumor responses, resulting in T cell dysfunction. Figuring out the mechanisms behind the effects tumors have on T lymphocyte antitumor responses has remained poorly understood.

Scientists from the University of Lausanne in Switzerland published a study in Nature Immunology where they found that reduced fitness of the cell’s powerhouse, the mitochondria, in tumor-infiltrating T lymphocytes was induced by the microenvironment of the tumor. These investigators found that supplementation with nicotinamide riboside (NR) enhanced T lymphocyte mitochondrial function and the antitumor response in mice.

Studies have shown that NR can boost levels of a molecule called nicotinamide adenine dinucleotide (NAD+), which is essential for cellular energy generation and genomic stability, to increase the healthspan and lifespan of mice as well as to prevent age-related diseases. Even so, researchers have presented different and sometimes conflicting views on the effects of boosting NAD+ levels on cancer.

The study in Nature Immunology demonstrated that impairments in tumor-infiltrating T lymphocyte function comes from the accumulation of dysfunctional mitochondria, cellular components that generate energy. In the cellular environment in proximity to the tumor (i.e., the tumor microenvironment), T lymphocytes accumulate mitochondria with compromised inner membranes, thin layers that compartmentalize the mitochondria, suggesting mitochondrial dysfunction.

(Yu et al., 2020 | Nature Immunology) The folds of the inner mitochondrial membrane (i.e., cristae) are increased in T lymphocytes present in normal spleens compared to tumors, indicating that the tumor microenvironment caused T cell mitochondrial dysfunction. (G) Cristae numbers and length are increased  in the T cells of normal spleens compared to tumors, illustrating that T cell mitochondria function is diminished by the tumor microenvironment. (H) The numbers of the inner membranes, the cristae, are significantly lower in T cells of tumors compared to T cells present in normal spleens. (I) The lengths of the cristae are significantly lower in T cells of tumors compared to T cells in normal spleens.

The team of researchers also found that accumulations of dysfunctional mitochondria in tumor-infiltrating T lymphocytes propelled the cells to a state of terminal exhaustion, locking them into a state of permanent dysfunction. When the scientists transplanted T cells from tumors to the spleen of mice, they found significantly less re-expansion of the transplanted T cells, indicating that the cells were in a state of progressive loss in their effector function (i.e., terminal exhaustion). These results indicated that T lymphocytes exposed to a tumor’s microenvironment enter a permanent cellular state of terminal exhaustion where they have reduced immunological function.

The research group then found that NR supplementation improved mitochondrial function and provided some degree of antitumor immunity. Since previous studies indicated that boosting NAD+ levels improve mitochondrial health, the group of scientists thought treating the mice with NR would prevent the tumor-infiltrating T lymphocytes from undergoing cellular exhaustion and stimulate antitumor immunity. Indeed, they found that NR supplementation improved mitochondrial health and enhanced the effects of PD-1, a checkpoint inhibitor that increased the T cell response to tumors, on tumor growth.

(Yu et al., 2020 | Nature Immunology) Nicotinamide riboside (NR) sustains mitochondrial fitness to enhance antitumor responses in T cells. NR potentially enhances antitumor immunity with treatment with PD-1, a checkpoint inhibitor protein that improves the T cell response to tumors.

“Treatment with nicotinamide riboside presents a promising strategy to prevent mitochondrial dysfunction,” stated the investigators in their study. Their study demonstrated that the microenvironments of tumors are associated with tumor-infiltrating T lymphocyte mitochondrial dysfunction, which leads to a permanent state of T cell exhaustion. The investigators say that these types of studies can provide critical information for improving T cell antitumor responses.