Multiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies

Esther Melamed, Michael William Lee, Esther Melamed, Michael William Lee

Abstract

Over the past two decades, the field of multiple sclerosis (MS) has been transformed by the rapidly expanding arsenal of new disease modifying therapies (DMTs). Current DMTs for MS aim to modulate innate and adaptive immune responses toward a less inflammatory phenotype. Since the immune system is also critical for identifying and eliminating malignant cells, immunosuppression from DMTs may predictably increase the risk of cancer development in MS patients. Compared with healthy controls, patients with autoimmune conditions, such as MS, may already have a higher risk of developing certain malignancies and this risk may further be magnified by DMT treatments. For those patients who develop both MS and cancer, these comorbid presentations create a challenge for clinicians on how to therapeutically address management of cancer in the context of MS autoimmunity. As there are currently no accepted guidelines for managing MS patients with prior history of or newly developed malignancy, we undertook this review to evaluate the molecular mechanisms of current DMTs and their potential for instigating and treating cancer in patients living with MS.

Keywords: cancer; cancer treatment; disease modifying therapy; multiple sclerosis; multiple sclerosis drug mechanism; multiple sclerosis treatment; treatment of autoimmune disease.

Copyright © 2020 Melamed and Lee.

Figures

Figure 1
Figure 1
Multiple sclerosis drug approval timeline.
Figure 2
Figure 2
S1P modulators. S1P modulators, Fingolimod and Siponimod, decrease egress of naïve memory, Th17, CD4/CD8 T cells, and plasma B cells from lymph nodes leading to a decreased inflammatory response and decrease in neurodegeneration via actions on the S1P receptors in lymph nodes, astrocytes and oligodendrocytes. S1P modulators also have actions on other cell types including cardiac myocytes contributing to first dose bradycardia. In cancer cells, S1P modulators activate pathways involved in cell cycle arrest and cell death via actions on histone deacetylases (HDACs) and cyclin/CDK cell cycle proteins. However, due to their effects on Bregs (increased) and T regs (decreased) there is a risk of increasing cancer incidence due to decreased immune surveillance.
Figure 3
Figure 3
(A,B) B cell therapies. B cell therapies play a role in the treatment of both multiple sclerosis and cancer, but yet can also promote cancer development. Rituximab targets CD20 found on the surface of immature (naïve) B cells (CD19/CD20+) leading to their destruction by several mechanisms including apoptosis, antibody-dependent cell cytotoxicity, and complement directed cytotoxicity. Rituximab also promotes the proliferation of T regulatory cells (Treg) and B regulator cells (Breg) which results in reduced inflammation. Rituximab has similar actions in the context of cancer, where elimination of CD19/CD20+ B cells leads to a reduction of tumor burden in patients with B cell malignancies, while elevations in Breg and Treg populations can promote possible tumor formation.
Figure 4
Figure 4
Dimethyl fumerate. Dimethyl Fumerate (DMF) ultimately enhances the activity of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) leading to transcription of anti-inflammatory genes, serving as the basis for DMF's beneficial effects in MS patients. In cancer cells, these same actions together with alterations in cell cycle protein and p53 expression, serve to attenuate cancer growth and proliferation. However, paradoxically DMF can also promote epithelial to mesenchymal transition (EMT) which enhances migration and metastasis. DMF may also alter the metabolic environment in cancer cells which aids their survival, growth, and proliferation.

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