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Page 226 Peixoto et al. Cancer Drug Resist 2018 2018;1:219-29 I http://dx.doi.org/10.20517/cdr.2018.17

was controlled by the HMT mixed lineage leukemia 1 (MML1) enzyme which catalyzes the trimethylation
of histone H3 lysine 4 (H3K4me3), and that targeted inhibition of HMTs, using Verticillin A, enhanced the
anti-PD-L1 response in these models.

Tumor antigen and future epidrugs/immunotherapies combinations
Most of tumor antigens are proteins normally expressed in the male germline lineage which are abnormally
expressed in tumor cells. These tumor antigens, whose the most studied are melanoma-antigen family A
and NY-ESO-1 (New York-esophageal squamous cell carcinoma-1), are presented by MHC-I on tumor cells
and are targets and activators of immune cells. Interestingly, epigenetic modifications have been linked
to the control of the expression of most of these antigens and demethylating agents or HDACi increased
[59]
their expression in various models (for a review, see ). For example, in in vitro cancer cells models
(glioma: U251 and mesothelioma: Meso96), repression of NY-ESO-1 gene expression was regulated by a
complex mechanism involving different DNMTs and HDAC1-including complexes which were recruited
[60]
sequentially . Combination of anti-disialoganglioside (GD2), which targets the tumor antigen GD2,
[61]
with vorinostat, one HDACi, also decreased neuroblastoma tumor growth in mice . In these tumors,
the HDACi treatment led to an increase in M2-like macrophage infiltration in the tumor but decreased
immunosuppressive MDSCs.

Moreover, MHC gene expression is also epigenetically controlled. Indeed, hypermethylation of MHC
promoters in melanoma was correlated with decreased antigen presentation. Immunoedition in cancers
could directly contribute to immunotherapy resistance since this process drives the selection of stem cell-
like immune cells associated with a high resistance to treatments. Indeed, the expression of the pluripotent
transcriptional factor NANOG in these cells can bind and activate the HDAC1 promoter and, consequently,
induce the deacetylation and repression of several target genes, such as NOXA, therefore leading to stem
[62]
cell-like phenotype and treatment resistance . Combining HDACi with immunotherapies in NANOG-
positive tumors may therefore limit cancer relapse and become a new line of treatment.

Stimulator of interferon genes (STING), is a protein normally activated by the cyclic GMP-AMP synthase
which detects exogenous cytosolic DNA following bacterial or viral cell infection or DNA release by tumor
cells. Expression of the lysine demethylase KDM5B has been shown to be inversely correlated to STING,
in ovarian cystadenocarcinoma, bladder urothelial carcinoma and breast invasive carcinoma and inversely
+
correlated to CD8 T-cell infiltration and survival, as well . This recent study also revealed that KDM5B
[63]
can demethylate histones and repress STING promoter and that this effect was specific since it was inhibited
by KDM5Bi. This new set of data suggests that KDM5Bi could be tested in the future to restore T-cell
infiltration and therefore improve anti-PD-1/PD-L1 treatments.

Transgenic TCR and epidrugs combination for future therapies
New protocols of engineering in immunology have recently allowed to develop novel cell-based
immunotherapies. Adoptive transfer of TCR transgenic T-cells has become a promising approach in the
field. For example, a protocol has been designed to target MART-1, which is a major antigen present in 95%
of melanomas, and therefore to design engineered T-lymphocytes which produce a transgenic TCR specific
of MART-1. However, it has been shown that these strategies had no effect on melanomas presenting a
resistance to BRAF inhibitors. Indeed, these cells present important defects in the apoptotic machinery
which impair TCR-induced apoptosis but it has also been shown that HDACi, such as SAHA, can regulate
apoptotic gene expression and restore TCR-induced tumor cell death. Even if the mechanisms and pathways
involved remain still unclear, preliminary results suggested that HDACi modulated the expression of
apoptotic genes, restoring the susceptibility of melanoma cells to apoptosis.