Table 2.

Immune system mechanisms of tumor evasion.

Target	Mechanism	Overview
Alterations in APCs	Inhibition of APC maturation and activation which impedes the appropriate co-stimulatory and cytokine signals to T cells and triggers the generation of regulatory T cells [20].	Different factors present in the tumor microenvironment such as IL-6, M-CSF, IL-10, VEGF, and TGF-β negatively regulate antigen-presenting cell functions [21].
	Selective increase in regulatory APCs that prevent immune responses by secreting TGF-β and stimulating the proliferation of regulatory T-cells [20].	Tumor microenvironment can induce a selective increase in the number of regulatory APCs, which can induce T-cell unresponsiveness by controlling T-cell polarity [20].
Dysfunction of effector cells	Enhanced proliferation of regulatory T-cells that suppress inflammation and regulate immune system activity.	Tumor microenvironment induces the proliferation of regulatory T-cells, which are able to inhibit T-cell proliferation and cytokine production, leading to immune suppression, which favors the immune escape of tumor cells [20].
	Induction of effector T-cells apoptosis through tumor-generated CD95L and activation of the T-cell CD95 receptor.	CD95 and CD95L are critical survival factors for cancer cells that protect and promote cancer stem cells [22]. Apart from suppressing the immune response, CD95L promotes tumor growth and invasiveness and triggers the acquisition of cancer stem cell phenotypes [22].
	Alterations in T-cell signal transduction after antigen stimulation which leads to a decreased response.	Alterations such as the decreased expression of CD3ζ, p56lck, and JAK-3, decreased mobilization of calcium signaling, inability to translocate NF-ĸB-p65, or decreased production of IL2 are frequently found in cancer patients [19].
Changes in tumor cells	Selection of tumor cells that are resistant to apoptosis, one of the hallmarks of cancer [17].	The pressure of immune surveillance or chemotherapeutic drugs enhances the selection and proliferation of cancer cells with mutations or alterations affecting one or various pathways controlling apoptosis.
	Alterations in HLA I expression.	Since the initiation of adaptive immune response occurs after T-cell receptor binding to antigen-loaded HLA-I presented by tumor cells, alterations in HLA-I expression, which is found in approximately 40–90% of human tumors derived from HLA-I positive tissues [23], impedes T-cell activation or causes loss of recognition.
	Alterations in the immune checkpoints.	After recognition of peptide antigen associated with the HLA-I, T-cell activation is controlled by co-stimulatory and co-inhibitory receptors and their ligands (immune-checkpoints). The over-expression of co-inhibitory molecules or the absence of co-stimulatory molecules typically leads to a T-cell exhausted phenotype.

CD95: Fas/APO-1. CD95L: CD95 ligand. APC: Antigen Presenting Cell/Dendritic Cell. HLA: Human Leukocyte Antigen. IL: Interleukin. JAK-3: Janus kinase 3. M-CSF: Macrophage Colony-Stimulating Factor. NF-ĸB: Nuclear Factor-kappa-B transcription complex. TGF: Transforming Growth Factor. VEGF: Vascular Endothelial Growth Factor.