Application of epigenetic-targeting agents to confer immune modulation in cancer

Although appraised at the prospect of revolutionising the cancer therapy landscape, immune therapy fails to benefit a substantial patient cohort. This partly occurs because cancer cells are proficient at adapting to changing conditions and reprogramming theimmune system's cancer-reactive status. In this scope, epigenetic events are critical facilitators of cellular int egrity and plasticity. In the prospect of counteracting such cancersustaining events, several epigenetic-targeting drugs have found application in the clinic, primarily in haematological cancers. Clinical efficacy in terms of cancer growth control
however leaves room for improvement, especially when implemented as a stand-alone treatment. Accordingly, the therapeutic scope of epigenetic-targeting drugs is anticipated to increase when combined with other therapies, including immune therapies. In the latter context, epigenetic-targeting drugs with putative immune-reprogramming effects could support the efficacy of immune therapies. Premising on this notion, this thesis examined the immune-reprogramming activity of epigenetic-targeted therapy in two cancer models: multiple myeloma and melanoma.

A first study reported on the immune-modulating aptitude of combined treatment with the DNA methyltransferase inhibitor Decitabine and the histone deacetylase inhibitor Quisinostat. Such combined epigenetic reprogramming increased the immunogenicity of multiple myeloma cells. Also, combination treatment changed the cancer microenvironment of myeloma-bearing mice in terms of immune cells’ presence and functional status. Combined epigenetic reprogramming conferred control over the expansion of myeloma cells in the bone marrow. The combination of Decitabine and Quisinostat thus offers prospects for reprogramming the immune-reactive status in multiple myeloma.

A second study reported on the immune-modulating aptitude of the epigenetic-targeting drug CM-272, whose innovative status ensues from its dual inhibitory effect on DNA methyltransferases and the histone methyltransferase G9a. CM-272 increased the antigenicity of melanoma cells, and in vivo-treated mice featured an immune-reactive transcriptome state. As such, CM-272 promoted the restrictive effect of cancer vaccination on melanoma outgrowth. Combined inhibition of DNA and histone methylation thus offers prospects for reprogramming the immunie-reactive melanoma to sustain cancer growth control by cancer vaccination.
Successful clinical application will rely on identifying context-specific optimal epigenetic-targeted therapy with a favourable balance between immune-stimulating and -inhibiting effects, combined with immune therapy attuned to the patient's immune status. Notably, epigenetic-dictated cellular plasticity is remarked to also apply to other cancerassociated cells including immune cells. Within the scope of immune cell-intrinsic epigenetic reprogramming, the therapeutic momentum of current epigenetic-targeting drugs is questioned. To attain the maximal therapeutic index for epigenetic reprogramming, optimisation strategies are discussed with respect to the design and mechanism-of-action of epigenetic-targeting agents as well as (pre)clinical experimental design. Finally, the epigenetic momentum of dendritic cells is discussed on account of improving the efficacy of cancer vaccine therapies via dendritic cell-targeted epigenetic reprogramming.