Mechanism of immune evasion in breast cancer

Figures & data

Figure 1 A summarized network of immune evasion mechanisms and their interactions.

Abbreviations: IL, interleukin; TGF-β, transforming growth factor type beta; NK, natural killer; CTL, cytotoxic T lymphocyte; MHC, major histocompatibility complex; DC, dendritic cell; PD-1, programmed death receptor 1; PD-L1, PD-1 ligand; FasL, Fas ligand; Fas, factor-associated suicide; HLA, human leukocyte antigen; BC, breast cancer; Treg, regulatory T cell; CCL, C–C motif chemokine ligand; STAT, signal transducer and activator of transcription; NF-κB, nuclear factor-kappa B; TNF-α, tumor necrosis factor alpha.

Table 1 Factors influencing the cellular apoptosis in breast cancer

Factors	Expression level	Impact on tumor development	Detailed impact on mechanism	References
Fas/FasL	Fas↓	Induce apoptosis	Activate apoptosis signaling and induce apoptosis in the cells in which this receptor interacts with its ligand – FasL	^Citation28
	FasL↑	Decrease immunity	Maintain a proapoptotic environment	^Citation29
			Induce effector T lymphocytes to death and stimulate activation-induced cell death and escape immune recognition and interference	^Citation8, ^Citation30
PD-1/PD-1L	↑	Inhibit apoptosis	Inhibit the activation of effector T cells, which induce FasL and interleukin-10	^Citation32
			Attenuate T cell apoptosis	^Citation34
			Stimulate tumor regression, improve the outcomes, and prove clinically effective when PD-1/PD-L1 pathway is targeted and PD-1 is blocked	^Citation46, ^Citation49^–^Citation51
Bcl-2	↑	Inhibit apoptosis	Inhibit the release of cytochrome C from mitochondria to the cytoplasm and the TRAIL-induced cellular apoptosis	^Citation55, ^Citation56
		Promote growth	Promote neoplastic transformation and prolong the life span of tumor cells by allowing them to accumulate oncogene mutations and stimulate the growth of BC cells	^Citation57, ^Citation58
Survivin	↑	Inhibit apoptosis	Associated with poorer outcome, advanced tumor grade, worse metastasis, and lower survival rate	^Citation59, ^Citation60
Caspase	↓	Promote apoptosis	Resist apoptosis by the downregulation of caspase activation	^Citation61

Notes: Various factors that can influence the programmed apoptosis are listed in the table along with their impacts on the cellular apoptosis in breast cancer. ↑ means upregulation and ↓ means downregulation.

Abbreviations: Fas, factor-associated suicide; FasL, Fas ligand; PD-1, programmed death receptor 1; PD-1L, PD-1 ligand; TRAIL, TNF-related apoptosis-inducing ligand; BC, breast cancer.

Figure 2 Influences of Fas/FasL system on apoptosis.

Note: This figure shows the way that Fas/FasL system applies to influence the apoptosis. In natural status, cells that can express Fas go through apoptosis after its combination to FasL in activated T cells. However, Fas is less expressed in BC cells and its specific intracellular signaling domain, the death domain (DD), is deficient. And the overexpression of FasL in activated T cells leads to T cells’ suicide.
Abbreviations: FasL, Fas ligand; Fas, factor-associated suicide; DD, death domain; BC, breast cancer.

Table 2 Interleukins associated with the immune evasion in breast cancer

Interleukins	Action on BC	Impact on tumor development	Impact on mechanism	References
IL-6	Promotion	Invasion↑ EMT	Take part in the activation of NF-κB signaling pathway by the activation of STAT3 and IL-6 receptor/GP130 complex, thus changing its phenotype to variants	^Citation103^–^Citation105
IL-10	Promotion	Angiogenesis↑ Invasion↑	Activate CTL and NK cells, increase tumor infiltration, and inhibit metalloproteinase	^Citation114
	Inhibition	Growth↓ Metastasis↓	Induction of NK-mediated lysis of BC
IL-18	Promotion	Tumorigenesis↑ Distal metastasis↑	Activate CTL and NK cells and induce IFN-γ	^Citation109, ^Citation110
	Inhibition	Local impact
IL-19 and IL-20	Promotion	Growth↑ Proliferation↑ Progression↑	Synthesis of matrix metalloproteinase	^Citation111, ^Citation112
IL-23	Promotion	Inflammation↑	Modulate infiltration of CD8^+ T cells and inflammation-related development of breast cancer microenvironment	^Citation113
IL-33	Tumor	Apoptosis of MDSC↓	Induce the autocrine production of GM-CSF Activate NF-κB and mitogen-activated protein kinase signaling	^Citation107

Notes: Different interleukins are listed in the table along with their influences on the immune evasion in breast cancer. ↑ means increase and ↓ means decrease.

Abbreviations: BC, breast cancer; IL, interleukin; NF-κB, nuclear factor-kappa B; STAT, signal transducer and activator of transcription; EMT, epithelial-to-mesenchymal transition; CTL, cytotoxic T lymphocyte; NK, natural killer; IFN-γ, interferon gamma; MDSC, myeloid-derived suppressor cell; GM-CSF, granulocyte–macrophage colony-stimulating factor.

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