Researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, have discovered a mechanism by which cancer patients' immune systems respond to chemotherapy. The new finding changes the current understanding of how the immune system responds to chemotherapy and could lead to opportunities for new treatments based on enhancing the body's immune response to the disease.
Chemotherapy for cancer is known to severely deplete the number of immune system T-cells, creating a condition known as lymphopenia. Paradoxically, lymphopenia leads to increased immune system response. It has not been clear how this happens. Some scientists have believed that chemotherapy-induced lymphopenia results in selective depletion of suppressor T-cells, a type of T-cell that acts to turn off or inhibit an immune response.
Depletion of suppressor T-cells increases immune response in cancer patients. However, this new study indicates that even though chemotherapy depletes T-cells, it does not selectively destroy suppressor or regulatory T-cells, as previously assumed. Instead, the study showed that the lymphopenia condition caused by chemotherapy actually provided a good environment for proliferation of suppressor T-cells that are believed to contribute to the ability of tumours to evade the body's immune system. The mechanism by which this occurs is not entirely clear, but could involve interleukin-2 (IL-2), a cytokine which was not previously associated with suppressing immune responses.
According to a NIH release, researchers at NCI's Center for Cancer Research (CCR), paediatric oncology branch, examined immune recovery in 26 young cancer patients with paediatric sarcomas (highly malignant tumours) who received cyclophosphamide-based chemotherapy, which depleted lymphocytes. The patients were then infused with their own frozen lymphocytes, which had been stored before chemotherapy had begun. Researchers examined the impact of this treatment on the patients' immune recovery with or without recombinant IL-2, an agent that has been considered capable of restoring an immune system weakened by chemotherapy.
"This is a surprising result, since IL-2 has been considered an immune activator not a suppressor. These results suggest that a large portion of IL-2's effects is to suppress immune responses. If, instead, a way could be designed to deplete the number of suppressor T-cells, that could create a chance for a different type of T-cell that attacks cancer cells to increase their numbers to fight the disease," said Crystal L Mackall, head of CCR's paediatric oncology branch immunology section and study co-author.
Such an opportunity may exist, as the researchers also discovered that the suppressor T-cells that appeared following chemotherapy and IL-2 administration were derived from existing T-cells, rather than being created anew in the patients' thymus glands, where T-cells typically originate. As a result, if one could deplete suppressor cells from the patient's system, these cells would not be efficiently regenerated.
Mackall explained. "If a patient with lymphocyte depletion were also depleted of suppressor cells, the immune system would be predicted to be highly reactive and responsive to antitumour vaccines and therefore may be better able to fight cancer."
The release further added that the study has important implications for developing future immunotherapies against cancer, as many researchers are interested in manipulating suppressor cells to make the immune system more effective in responding to cancer.
"This study provides the first insight into what makes regulatory T-cells tick and therefore provides ideas for new ways to deplete or manipulate these cells more effectively in humans," Mackall added.
CCR's paediatric oncology branch is planning a follow-up clinical trial that will attempt to rebuild the immune system in a similar set of patients who are depleted of suppressor T-cells and also will be administered a tumour vaccine.