Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.
Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.
The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.
Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.
The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).
The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.
When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.
In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.
The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.
The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.
When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.
The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.
The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.
From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.
This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.
