New findings reported in Nature Immunology highlight how the tumor microenvironment attacks the mitochondria of T lymphocytes, the cells that lead to anticancer immune responses. The study comes from Ludwig Cancer Research.
The mitochondrial dysfunction that occurs from a tumor’s microenvironment is called terminal exhaustion. Understanding this mitochondrial state and the condition that provokes it could lead to new targets in drug development.
"T lymphocytes often have a high affinity for antigens expressed by cancer cells," says Ludwig Lausanne Associate Member Ping-Chih Ho. "This means that, in principle, they should attack cancer cells vigorously. But we often don't see that. People have always wondered why because it suggests that the best soldiers of the immune system are vulnerable when they enter the battlefield of the tumor. Our study provides a mechanistic understanding of why this happens and suggests a possible strategy for preventing the effect that can be quickly evaluated in clinical trials."
"Our functional analysis revealed that those T cells with the most depolarized mitochondria behaved most like terminally exhausted T cells," said Ho. The issue, then, say the researchers, is that in a tumor microenvironment, T lymphocytes do not remove and digest depolarized mitochondria through mitophagy, so the broken down mitochondria just build up. "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.
Ho and other Ludwig researchers saw that a nutritional supplement called nicotinamide riboside (NR) can help T lymphocytes out of terminal exhaustion by inducing mitophagy and creating the space for new mitochondria – which ultimately strengthen their immune system response. "We have shown that we may be able to use a nutritional approach to improve checkpoint blockade immunotherapy for cancer," said Ho. This response was shown in tumors in mouse models of melanoma and colon cancer.
The team continues their investigations with the hope that better understanding the signals from depolarized mitochondria could improve cancer immunotherapy treatment development.