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. The study findings appear in Nature Medicine*, November 2005.

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 tumors 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.

Researchers at NCI's Center for Cancer Research (CCR), Pediatric Oncology Branch, examined immune recovery in 26 young cancer patients with pediatric sarcomas (highly malignant tumors) 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. The cancer patients in the study were assigned to one of three groups: the first group received moderate-dose IL-2 therapy; the second group received low-dose IL-2 treatment, and the third group received no IL-2. The researchers reported that the patients who received IL-2 - at either dose - showed a marked increase in suppressor T-cells after chemotherapy. These findings were confirmed in a parallel study in lymphopenic mice.

"This is a surprising result, since IL-2 has been considered an immune activator - not a suppressor," commented Crystal L Mackall, M.D., head of CCR's Pediatric Oncology Branch Immunology Section and study co-author. "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, she added.

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 antitumor vaccines - and therefore may be better able to fight cancer."

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 Pediatric 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 tumor vaccine. "We hope that this setting will lead to very vigorous antitumor immune responses that can prevent tumor recurrence," Mackall said.

For more information about cancer, visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4 CANCER (1-800-422-6237).

* Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA, Long LM, Bernstein D, Hill BJ, Douek DC, Berzofsky JA, Carter CS, Read EJ, Helman LJ, Mackall CL. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nature Medicine, Vol. 11, No. 11.

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