The immunomodulatory effects of endocrine therapy in breast cancer

Huang, Huanhuan; Zhou, Jun; Chen, Hailong; Li, Jiaxin; Zhang, Chao; Jiang, Xia; Ni, Chao

doi:10.1186/s13046-020-01788-4

Journal of Experimental & Clinical Cancer Research

Table 1 The effects of different endocrine therapeutic strategies on immune cells

From: The immunomodulatory effects of endocrine therapy in breast cancer

Therapeutic strategy	Subdivision	Drug/inhibitor	Modulate TIM component	Effects on immune cells
Anti-estrogenic drugs	Selective estrogen receptor Modulators (SERMs)	tamoxifen, toremifene, raloxifene	CD8+T cells	proliferation↑ [35], cytotoxicity↓ [12]
			CD4+T cells	Treg polarization↑ [12]
			NK cells	cytotoxicity↑ [36]
			DCs	functional differentiation and immunostimulatory capacity↓ [37]
			neutrophils	tamoxifen improves the proinflammatory pathway [38], while raloxifene has the opposite effect [39]
	Selective estrogen receptor down-regulators (SERDs)	fulvestrant	CD8+T cells	cytotoxicity↓ [12], tumor infiltration↑ [40]
			CD4+T cells	Treg polarization↑ [12], tumor infiltration↑ [40]
			MDSCs, Tregs	tumor infiltration↓ [40]
			DCs	tumor infiltration↑ [40]
	Aromatase inhibitors (AIs)	letrozole, anastrozole, exemestane, formestane	CD8+T cells	tumor infiltration↑ [41]
			CD4+T cells	Treg polarization↓ [42]
			Tregs	ERβ inactivation induces immunosuppressive activity↓ [43]
			mast cells	ERβ inactivation induces CCL-2 production↓ [44]
	Gonadotropin-releasing hormone antagonists (GnRHa)	Goserelin triptorelin	T cells	induce TH1 shift [45]
Inhibition of the PI3K-AKT-mTOR pathway	PI3K inhibitors	pan-PI3K inhibitor	macrophages	proinflammatory cytokines production and motility↓ [46]
			Tregs	proliferation↓ [47]
			T cells	cytokines and granzyme B secretion↓ [48], tumor infiltration↑ [49]
			NK and B cells	tumor infiltration↑ [49]
		p110α inhibitor	CD8+ T cells	tumor infiltration↑ [50], cytokines production and cytotoxicity↑ [51],
			CD4+ T cells	cytokines production↑ [51], Treg polarization↓ [51]
			MDSCs	tumor infiltration↓ [52]
		p110β inhibitor	macrophages	phagocytosis↓ [53]
		p110β inhibitor	neutrophils	cell adhesion, spreading and ROS formation↓ [54]
		p110γ inhibitor	myeloid cells	tumor infiltration↓ [55]
			macrophages	M1 polarization↑ [56]
			CD8+T cells	PD-1 and CTLA-4 expression↑ [57], tumor infiltration↑ [49]
			CD4+Tcells, B cells	tumor infiltration↑ [49]
		p110δ inhibitor	macrophages	tumor infiltration↓ [58]
			MDSCs, Tregs	immunosuppressive function↓ [59]
			T cells	effector response of effector/memory T cells↓ [60]
			B cells	proliferation, survival and differentiation↓ [61]
	AKT inhibitors	capivasertib	Tregs	proliferation↓ [47]
			MDSCs	differentiation and viability↓ [62]
			macrophages	AKT1 ablation →M1 phenotype, AKT2 ablation →M2 phenotype [63]
	mTOR inhibitors	rapamycin, everolimus	mononuclear cells	polarization towards M1 macrophage
			macrophages	proinflammatory cytokine production and motility↓ [46]
			NK cells	proliferation and cytotoxicity↓ [64, 65]
			DCs	CD40, CD86↑, PD-L1↓ [66]
			CD8+ T cells	anergic state induction [67, 68], tumor infiltration↓ [69]
			CD4+ T cells	induce Tregs polarization and Foxp3 stable expression [70]
			γδT cells	cytotoxicity of Vγ4γδT cells↑ [71], proliferation and cytotoxicity of Vγ2Vδ2 T cells↑and apoptosis↓ [72]
			Tregs	transient mTOR inhibition: reverse the hyporesponsiveness [73] chronic mTOR inhibition: proliferation↓, suppressive function↓ [73, 74]
Inhibition of the cell cycle	CDK4/6 inhibitors	abemaciclib, palbociclib, ribociclib	myeloid cells	tumor infiltration↓ [75]
			macrophages, DCs	antigen presentation↑ [76]
			T cells	PD-1 and CTLA-4 expression↑ [52], activation↑, IL-2 production↑ [75]
			Tregs	inhibition of the cell cycle [77]

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ISSN: 1756-9966

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