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Torres et al. J Cancer Metastasis Treat 2018;4:4 I http://dx.doi.org/10.20517/2394-4722.2017.49 Page 3 of 25

Figure 1. Immunosurveillance vs. immunoediting: key points in regulation of immune system in tumor progression/regression. Immunoediting
comprises 3 phases: (A) elimination: when the tumorcells begins to proliferate, an inflammatory response is induced by the injured tissue.
This causes the migration of cells from the immune system, orchestrating the innate immune response; (B) the equilibrium phase: in which
this continuous process produces a selective pressure in these cells that can cause genetic or epigenetic rearrangement, causing certain
cells to evade these immunological effector mechanisms; (C) the escape phase, when cells that have evaded these mechanisms also gained
uncontrolled growth ability. DC: dendritic cells; MHC: major histocompatibility complex; NK: natural killers

[28]
+
T lymphocytes (T-CD8 ) are the main mediators in this process ; macrophages associated to tumors,
dendritic cells (DC), naïve T cells, aβT-cell receptor (TCR)-expressing T cells, γδT-cells and regulatory
+
T cells (T-reg) FOXP3 also participate in the immune response towards the tumor. They interact
with tumor cells, while some act inhibiting their growth and others stimulate it, composing the tumor
[29]
microenvironment .

NK cells are considered the main part of the innate immunity against tumors. They recognize and eliminate
neoplastic cells effectively [30,31] ; but are not confined to the innate immune system. They also act with the
[32]
adaptive immunity by working as T-lymphocyte response modulators . Damage associated molecule patterns
[34]
[33]
(DAMPs) are released from tumor cell elimination mediated by NK cells , increasing DC maturation and
[35]
+
presentation to T-CD8 lymphocytes on major histocompatibility complex (MHC)-1 molecules . Once
+
activated, NK cells and T-CD8 lymphocytes induce activation, proliferation and recruiting of other
[36]
cells to the tumor site . This is achieved through the release of cytokines such as interferon gamma
(IFN-γ), granulocyte and macrophage colonies stimulating factor (GM-CSF) and tumor necrosis factor
[37]
(TNF) . IFN-γ carries important functions such as direct inhibition of tumor growth, macrophage
+
activation, and increases Th1 expression among T-CD4 lymphocytes. This represents their major
+
[38]
role in modulating cellular response against tumors . T-CD8 lymphocytes require the expression of
tumor antigens on MHC-1 molecules and co-stimulatory signals in the tumor site in order to function
appropriately .
[39]
Cancer may become clinically detectable in advanced stages explained by the mechanisms in which tumor
[41]
[40]
cells evade immune surveillance . This theory started with the “immunoediting” process , where the
immune system works inversely: making an immunosuppressed environment that favors tumor growth.
This process is composed by three phases: elimination, equilibrium, and escape [Figure 1], being the
[42]
elimination phase a homologous mechanism from those seen in immunosurveillance .