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Page 220 Peixoto et al. Cancer Drug Resist 2018;1:219-29 I http://dx.doi.org/10.20517/cdr.2018.17

Figure 1. Examples of direct implication of epigenetic modifications in immune recognition of cancer cells. Epigenetic modifications:
DNA methylation (white circles) histone methylation (me) and histone acetylation (Ac, +) are directly implicated in: (1) chemotaxis
by the regulation of the expression of CXCL9/10; (2) in immune checkpoint control, by the regulation of PD-L1 and PD-1 in cancer cells
and CD8+ cells respectively; and in (3) antigen presentation, by the control of the expression of CTAs and MHC-I. CXCL: C-X-C motif
chemokine ligand; PD-1: programed cell death 1; PD-L1: PD-1 ligand; CTA: cancer testis antigen; TCR: T-cell receptor

activation of immune system effectors and the consequent elimination of the cancer cells. Indeed, an
+
increase in the recruitment of cytotoxic CD8 T-lymphocytes into the tumor is mediated by chemokines
such as C-C motif chemokine ligand 5, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL10 and is
[1-3]
correlated to lower metastasis risk and better outcome for patients [Figure 1]. Three sequential phases of
immune edition of cancers have been described and summarized under the rule of the “3E”: (1) Elimination;
[4]
(2) Equilibrium; and (3) Escape . During the Elimination phase, some newly transformed cells can be
quickly eliminated by immune effector cells, such as natural killers (NKs), but this phase can also favor
the development of heterogeneous tumor cancer cells resulting in the selection of new variants resistant to
immune edition. Further growth of cancer cells selected during the Equilibrium phase may then lead to the
acquisition of aggressive phenotypes and resistance to immune system elimination inducing clinical lesions.
So, immune escape has now been included as one of the new hallmarks of cancer development described
[5]
in the revised version of Hanahan and Weinberg in 2011, together with resistance to cell death, replicative
immortality or induced angiogenesis, for example.

RESISTANCE TO IMMUNOTHERAPY IN CANCERS
Immunotherapy protocols are designed to annihilate immune escape in cancer cells and restore elimination
of cancer cells. In 2018, Nobel Prize in medicine awarded James P. Allison and Tasuku Honjo for their work
on the knowledge of immune edition and the development of immunotherapies to fight against cancer
[6,7]
cells . Immunotherapies include: cancer vaccines, humanized monoclonal antibodies targeting TAAs,
transfer of chimeric antigen receptor-T-cells or adoptive transfer of transgenic TCR-expressing T-cells.
Nevertheless, immunotherapy resistances have been described in patients and are divided in innate and
[8]
acquired resistance (for a review ). Intrinsic resistance is frequently observed in patients with a failure
of systemic immune response such as immune-compromised HIV patients or specific failures induced
for example by a lack of expression of specific tumour antigens by tumour cells. Adaptive resistance
might be provoked by several processes [Figure 1]: (1) loss of antigens presentation due to mysfunctions