Fingolimod blocks immunosurveillance of myeloma and B-cell lymphoma resulting in cancer development in mice

To the editor:

Fingolimod (FTY720, 2-amino-2-propane-1,3-diol hydrochloride) is a remarkably efficient immunosuppressive drug that was recently approved as the first oral treatment for multiple sclerosis. Fingolimod prevents lymphocyte egress from lymph nodes by targeting 4 of 5 sphingosine-1-phosphate receptors.¹  Two phase 3 trials showed that fingolimod significantly reduced multiple sclerosis disease progression compared with placebo or standard treatment.^2,3  However, both trials concluded that longer studies were required to assess possible long-term risks.^2,3  Reports from studies in mice and humans strongly support a crucial role of lymphocytes and adaptive immunity in both preventing cancer and fighting established tumors in a process called cancer immunosurveillance.^4,5  In transplant recipients, lifelong immunosuppressive treatment is associated with an increased risk of cancer.⁶ 

We investigated the effect of fingolimod on cancer immunosurveillance mediated by tumor-specific CD4⁺ T cells in mouse models for myeloma and B-cell lymphoma. We used severe combined immunodeficient (SCID) mice made transgenic for a T cell receptor (TCR) that recognizes a tumor-specific idiotypic (Id) antigen that is secreted by MOPC315 myeloma and F9 B-cell lymphoma.^7,8  The Id-specific TCR-transgenic SCID mice are resistant against subcutaneous challenge with MOPC315 and F9 cells. The protection is Id-specific, CD4⁺ T cell–mediated and does not require the presence of B cells and CD8⁺ T cells.^7,8  On cancer cell inoculation, Id-specific CD4⁺ T cells first become activated in the draining lymph nodes where they acquire a T helper type 1 (Th1) phenotype. Id-specific Th1 cells then migrate to the incipient tumor site and secrete IFN-γ, resulting in local activation of macrophages which become tumoricidal and eradicate the cancer cells.^9,10 

Id-specific TCR-transgenic SCID and control nontransgenic SCID mice were inoculated with cancer cells and treated daily with fingolimod or vehicle only. Fingolimod efficiently blocked rejection of both MOPC315 myeloma and F9 B-cell lymphoma by TCR-transgenic mice (Figure 1A-B). Fingolimod had no effect on the survival of control nontransgenic SCID mice inoculated with MOPC315 (Figure 1C). Fingolimod did not block activation of tumor-specific CD4⁺ T cells in the draining lymph nodes, as defined by up-regulation of CD69 (Figure 1D). In contrast, fingolimod strongly inhibited migration of tumor-specific CD4⁺ T cells to the incipient tumor site (Figure 1E). Furthermore, fingolimod prevented Th1-mediated activation of tumor-infiltrating macrophages, as measured by up-regulation of surface major histocompatibility (MHC) class II molecules. In fact, in TCR-transgenic mice treated with fingolimod, tumor-infiltrating macrophages had surface MHC class II levels that were as low as those of macrophages from T cell–deficient SCID mice (Figure 1F). Thus, the data strongly suggest that fingolimod blocks immunosurveillance of B-cell cancers by suppressing migration of tumor-specific Th1 cells from lymph nodes to the incipient tumor site, thereby preventing Th1-mediated activation of tumoricidal macrophages.

In summary, fingolimod is a strong immunosuppressive drug which blocks immunosurveillance of myeloma and B-cell lymphoma by CD4⁺ T cells in experimental mouse models, resulting in cancer development. Further studies are required to determine the effect of fingolimod on other immune cells involved in cancer immunosurveillance such as CD8⁺ T cells and NK cells.⁴  In our experiments, mice were treated with rather high doses of fingolimod (1-2 mg/kg bodyweight/d) to efficiently block sphingosine-1-phosphate receptors. Patients receive much lower doses (0.5-1.25 mg/d) but for longer time periods (years). Therefore, our findings cannot be directly translated to patients. However, the data suggest that long-term treatment with fingolimod may potentially lead to increased risk of cancer in humans.