NR Can Enhance T Cell Antitumor Immunity by Restoring Mitochondrial Function

Cancer

T lymphocytes that infiltrate and suppress tumors progressively lose their ability to function, but nicotinamide riboside (NR) supplementation enhances T cell mitochondrial fitness to sustain the antitumor response.

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.

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Recently, 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.

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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.

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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.

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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.

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(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.

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