Mimicking Fasting During Chemotherapy Enhances T Cell Activity in Preclinical Study
Fasting during chemotherapy treatment helps increase the presence of cancer-killing T cells, according to 2 new independent studies. In these studies, tumor masses were smaller over time in mice that received chemotherapy combined with a fasting-mimicking diet or caloric restriction mimetics alone compared with masses in mice that received only chemotherapy.1,2
These 2 papers demonstrate strategies to exploit tumor cells' weakness to caloric restriction and enhance immune-mediated cancer cell death. However, more study is needed to understand if mimicking fasting improves outcomes for other types of cancer treatments, including emerging immunotherapies. Also, it is still unknown if these results can be replicated in humans; these studies are currently proof of concepts.
The study of a fasting-mimicking diet sought to confer the benefits of starvation without the negative side effects. Mice with breast or skin cancer were fed a low-sugar, low-protein, high-fat, low-calorie diet and were observed for 6 weeks while receiving doxorubicin, cyclophosphamide, or no chemotherapeutic drugs. All of the mice receiving the diet-drug combination saw their tumors shrink to half the volume of the tumors in mice that received chemotherapy alone.
"Our main finding is that the T cells are essential for the toxicity of the fasting plus chemotherapy to cancer cells," said Valter Longo, PhD, a gerontologist and cell biologist of the University of Southern California Longevity Institute and FIRC Institute of Molecular Oncology in Italy. "The biggest factor exposing cancer cells to the T cells is the effect on the enzyme heme oxygenase-1, which is normally at high levels in cancer cells. Fasting reduces oxygenase levels and gives rise to a number of changes that included the increase of tumor-killing cytotoxic T cells."
The other study used caloric restriction mimetics, which are drugs that selectively trigger some of the biochemical cascades that result from starvation but without the weight loss, and this instigated the same chemotherapy-sensitizing effects from T cells. Hydroxycitrate was the mimetic used here. After mice with transplanted lung and breast cancers received hydroxycitrate, tumor numbers and size were reduced. Furthermore, the researchers observed the T cells responding to the pharmacological starvation of the cancer cells, which changed the tumor microenvironment to increase the formation of new white blood cells.
"My theory is that when you cause some cancer cell death, you stimulate the release of factors that enhances the recruitment of cell types that can fight against the tumor and reduce the immunosuppressive cells," said Guido Kroemer, MD, PhD, a cell biologist and cancer researcher of INSERM and the Centre de Recherche des Cordeliers in Paris, France. "But we haven't excluded that the death of immune cells themselves would also contribute to the effect of caloric restriction mimetics in reaction to chemotherapy."
The next steps are long-term studies to demonstrate that these strategies can be effective in humans.
1. Pietrocola F, Pol J, Vacchelli E, et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell. 2016;30(1):147-160.
2. Di Biase S, Lee C, Bandhorst S, et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell. 2016;30(1):136-146.