Langerhans cell hetiocytosis is a rare form of cancer that affects dendritic cells. This type of white blood cell helps to protect against infections. LCH is currently treated with chemotherapy. However, less than half of the patients are cured by this treatment.Dr. Rikhia Chhakborty, assistant professor of pediatrics - hematology and cancerology at Baylor College of Medicine, stated that "our research team focuses primarily on identifying the causes of LCH in order to develop better treatments for patients."LCH lesions do not contain abnormal dendritic cell populations. Instead, most cells are invading immune cells such as T cells that are recruited to the sites of disease. It is unknown how T cells and other immune cell contribute to LCH disease. Chakraborty and her colleagues at Texas Children's Cancer Center Histiocytosis Program identified the types and activity of immune cells involved in LCH lesion.Chakraborty stated, "We wanted to understand how the immune microenvironment is constructed in LCH and why there are accessory immune cells." "Is it possible that they are trying to help but can't? Are they being influenced by diseased cells in order to worsen the situation?Understanding the immune microenvironment of LCHThere are two main types of T cells: the one that fights and kills, the cytotoxic T cell, and the other that helps to keep the immune system in control, the regulatory T cell. Chakraborty and his team discovered that LCH lesion formation is more likely to have both regulatory and cytotoxic T cells. The cytotoxic T cell are paralyzed, a condition known as "exhaustion", and they are not effective in preventing LCH lesions from forming.AdvertisementA viral infection is usually associated with exhausted T cells. The immune system signals the T cells to stop fighting after the infection has been cleared. The T cells display a protein on the surface of their cells to signal that they have given up fighting and are ready for rest. The LCH is where the diseased cells trick T cells into entering an exhausted state. They trigger programmed cell death protein 1 receptors (PD-1), which are an immune checkpoint protein that shuts down the T cells and prevents an attack against cancer cells.Chakraborty stated that exhausted T cells do not become permanently damaged. These T cells can be overcome by therapies that disable the PD-1 receptor.Combining therapies yields promising resultsEarly trials that treated LCH patients with drugs that block LCH's growth pathway (MAPK pathway), showed rapid improvement in LCH lesions. Although some responses are incomplete, lesions almost always return to their original state after treatment is ended.Chakraborty's team has identified a new treatment option for LCH that targets the inflammatory immune system. This new approach uses immunotherapy to attack the PD-1 receptors, which incapacitate T cells. It also includes MAPK inhibition to target dendritic cell-causing disease. This combination of therapies would prove to be more effective than either therapy alone, they concluded.The researchers used murine models of LCH created in collaboration with Dr. Miriam Merad at Icahn School of Medicine, Mount Sinai to measure the response to anti-PD-1 and MAPK inhibitor treatments alone.The team noticed a decrease in diseased LCH cell count in models treated with MAPK inhibitors, but no infiltration of T cells. The team saw the opposite in models treated with anti-PD-1. There was a decrease in infiltrating cells, but no reduction in diseased LCH cell populations. Chakraborty's team saw a significant drop in both infiltrating and diseased LCH cell counts in the combined therapy model.Chakraborty stated that combination therapy produced a synergistic response and a significantly lower disease burden than monotherapy. The results are encouraging and suggest that combined MAPK/checkpoint inhibitors could be a viable therapeutic strategy for future clinical and preclinical trials of LCH.Chakraborty said that clinical trials of combination therapy could provide hope for patients with relapsed diseases. She said that combination therapy could reduce toxicities seen in the current standard treatment.
