Immunotherapy, in which programmed immune cells are used to selectively destroy cancer cells, has revolutionized cancer treatment. However, cancer cells have developed strategies to evade the immune system, leading to poor treatment outcomes. Now researchers from Japan have identified the transfer of mitochondria with mutated DNA from cancer cells to immune cells as a key mechanism of immune evasion and resistance to immunotherapy. Combating this transfer could increase the effectiveness of cancer immunotherapy.
Researchers Discover Mitochondrial Transfer Between Cancer Cells and Immune Cells as an Important Strategy to Evade the Immune System
The immune system plays a key role in recognizing and destroying cancer cells. Cancer immunotherapy works by programming immune cells to recognize and eliminate cancer cells. However, many cancers can evade immune surveillance through various mechanisms, leading to resistance to treatment. This underscores the need to better understand the molecular processes that enable immune evasion. The tumor microenvironment (TME) – the space surrounding a tumor – plays a critical role in the interactions between cancer and immune cells. Cancer cells can reshape the TME to their advantage and weaken tumor-infiltrating lymphocytes (TILs), the immune cells that attack the tumor.
Mitochondria, also known as the “powerhouses of the cell”, are small organelles that produce energy for various cellular processes. They play an important role in the metabolic reprogramming of cancer cells and tumor-infiltrating lymphocytes. However, the exact mechanisms underlying mitochondrial dysfunction and its effects on the tumor microenvironment are poorly understood. To fill this knowledge gap, a team of researchers led by Professor Yosuke Togashi from Okayama University in Japan has gained new insights into mitochondrial dysfunction in cancer immune evasion. In collaboration with Tatsuya Nishi and Tomofumi Watanabe from Okayama University and Hideki Ikeda, Katsushige Kawase and Masahito Kawazu from the Chiba Cancer Center Research Institute, the team identified mitochondrial transfer as a key mechanism of immune evasion. Prof. Togashi explains: “We have discovered mitochondrial transfer as one of the key mechanisms of immune evasion. Our research adds a new dimension to the understanding of how tumors resist immune responses, potentially leading to the development of more comprehensive and tailored approaches in the treatment of various cancers.”
Mitochondria carry their own DNA (mtDNA), which encodes proteins that are crucial for energy production and transfer. However, mtDNA is susceptible to damage, and mutations in mtDNA can promote tumor growth and metastasis. In this study, the researchers examined TILs from cancer patients and found that they contained the same mtDNA mutations as the cancer cells. Further analysis revealed that these mutations were associated with abnormal mitochondrial structures and dysfunction in TILs. Using a fluorescent marker, the researchers tracked the movement of mitochondria between cancer cells and T cells. They found that mitochondria were transferred via direct cell-to-cell connections, so-called tunnel nanotubes, as well as through extracellular vesicles. Once inside the T cells, the cancer-derived mitochondria gradually replaced the original T cell mitochondria, leading to a condition called “homoplasmy” in which all mtDNA copies in the cell are identical.
New Findings Could Pave the Way for More Effective Therapies in the Future
Normally, damaged mitochondria in TILs are removed by a process called mitophagy. However, mitochondria transferred from cancer cells appeared to resist this degradation. The researchers discovered that factors that inhibit mitophagy and thus prevent its degradation were also transferred with the mitochondria. As a result, mitochondrial dysfunction occurred in the TILs, leading to reduced cell division, metabolic changes, increased oxidative stress and an impaired immune response. In mouse models, these dysfunctional TILs also showed resistance to immune checkpoint inhibitors, a type of immunotherapy.
By identifying mitochondrial transfer as a novel mechanism to bypass the immune system, this study opens up new possibilities to improve cancer treatment. Blocking mitochondrial transfer could improve immunotherapy response, especially in patients with treatment-resistant cancers. Cancer therapies are often associated with high costs and significant side effects, especially when they are ineffective. Increasing the success of immunotherapy by inhibiting mitochondrial transfer could reduce the burden of cancer and improve treatment outcomes for patients. This discovery offers exciting new insights into cancer biology and could pave the way for more effective therapies in the future.