Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche

Figures & data

Figure 1 Immune landscape in Barrett’s Esophagus. Influenced by environment factors, several immune cells and cytokines are involved in the progress of BE microenvironment. Cytokines IL-1B, IL-4, and IL-6 can activate cardiac stem cells to promote columnar metaplasia. Cytokine IL-6 can promote the anti-apoptosis of Barrett epithelial cells through the IL-6/STAT3 pathway. TNF-α can promote angiogenesis and the expression of oncogene c-myc by upregulating the expression of IL-8 and β-catenin, respectively. The proportion of overall immune cells and the ratio of Th1/Th2 in the BE microenvironment decreased significantly. MMP-7, MMP-9, and MMP-13 are up-regulated in BE epithelial cells and can promote cell migration and matrix remodeling.

Figure 2 Immune landscape of ESCC tumor microenvironment.

Table 1 The Role of Hypoxia and Acidosis in the TME of Esophageal Carcinoma

Entry	Cancer Type	Finding	Effects on Tumors	Ref.
Hypoxia and acidosis	ESCC	Induction of high expression of GLUT-1 in response to hypoxia and insufficient energy supply	Acceleration	[^Citation35]
	ESCC	Regulation of the expression of the key aerobic glycolytic enzyme PKM2 through the mTOR pathway	Acceleration	[^Citation43]
	ESCC	The induction of high expression of CAIX maintains intracellular pH stability and promotes tumor cell invasion and migration	Acceleration	[^Citation46^–^Citation48]
	EC	ATP6V0C up-regulates glycolytic enzyme expression and increases extracellular acidification rate through interaction with PKM2	Acceleration	[^Citation49]
	ESCC, EC	HIF-1α and VEGF synergistically induce angiogenesis	Acceleration	[^Citation50^–^Citation54]
	ESCC	HIF-1α specifically binds to the SP1 promoter and regulates its transcription program, thereby enhancing migration and invasion	Acceleration	[^Citation55]
	ESCC	HIF-1α can bind to the hypoxic response element upstream of the IGFBP3 transcription initiation site, and then induce continuous translation of IGFBP3 mRNA and promote growth and proliferation through the insulin-like growth factor-independent pathway	Acceleration	[^Citation44,Citation56]
	EC	HIF −1 directly binds to specific hypoxic response elements of the EMMPRIN promoter to promote EC cell migration and epithelial-mesenchymal transition	Acceleration	[^Citation57]
	EC	HIF-1α can stimulate EC infiltration and metastasis by inhibiting E-cadherin and promoting MMP-2 expression	Acceleration	[^Citation58]
	ESCC	Up-regulation of exosomes in ESCC promote angiogenesis and PD1 + TAM expansion	Acceleration	[^Citation64,Citation68,Citation69]
	ESCC	MicroRNA-21 in exosomes induces chemotherapy resistance, promotes migration and invasion	Acceleration	[^Citation70^–^Citation72]
	ESCC	MicroRNA-212 in exosomes promotes epithelial-mesenchymal transition and ECM degradation	Acceleration	[^Citation73]

Table 2 The Role of Myeloid Cells in the TME of Esophageal Carcinoma

Entry	Cancer Type	Finding	Effects on Tumors	Ref.
MDSCs	EC	The tumor-associated gene MAEL over-expresses and up-regulates IL8 to recruit PMN-MDSCs, while the recruited PMN-MDSCs can up-regulate MAEL expression through the TGF-β/Smad pathway	Acceleration	[^Citation90]
	EC	Th2 derived cytokines IL-4, IL-6 and IL-13 can significantly enhance the immunosuppressive function of MDSCs in EC by inducing the expression of ARG1	Acceleration	[^Citation81,Citation89,Citation91]
	EC	MDSCs overexpressing CD38 have stronger activated T cell immunosuppressive and tumor-promoting functions, and this effect can be inhibited by CD38 monoclonal antibody Daratumumab	Acceleration	[^Citation92]
TAMs	ESCC	GDF15 derived from TAMs activate TGF- βRII receptor in cancer cells to induce the PI3K/Akt and MEK/Erk pathways to increase proliferation and migration	Acceleration	[^Citation100,Citation101]
	ESCC	Macrophage-derived IL-8 binds to CXCR1 and CXCR2 of ESCC cells and phosphorylates Akt and erk1/2 pathways to promote tumor migration and invasion	Acceleration	[^Citation102]
	ESCC	Cyr61 can be expressed in ESCC cells and TAMs, which promotes macrophage migration and CD204 expression in macrophages through the MEK/ERK pathway	Acceleration	[^Citation105]
	ESCC	CD204+TAM induced increased expression of ANXA10 in cancer cells and promoted ESCC cell proliferation through phosphorylated Akt and erk1/2 pathway	Acceleration	[^Citation106]
	EAC	Different TAMs subpopulations play diverse tumorigenic functions in EAC	Acceleration	[^Citation113]
DCs	EC	LAMP-3 can be expressed instantaneously when the DC is mature and can be regarded as a specific marker of mature DC, indicating a good prognosis	Inhibition	[^Citation115^–^Citation117]
	EC	DC vaccine can improve the cytotoxicity of CTL and indirectly exert anti-tumor effect	Inhibition	[^Citation126^–^Citation128]

Table 3 The Role of Lymphocytes in the Tumor Microenvironment of Esophageal Carcinoma

Entry	Cancer Type	Finding	Effects on Tumors	Ref.
CD8+T cell	ESCC, EAC	The infiltration of CD8+ T cells in both ESCC and EAC predicted a favorable prognosis.	Inhibition	[^Citation136]
	ESCC	IDO may inhibit T lymphocyte proliferation by mediating tryptophan catabolism	Acceleration	[^Citation138^–^Citation140]
	ESCC	PD-L1 expressed in tumor cells binds to PD-1 on the surface of T cells to escape CTL cytotoxic effects	Acceleration	[^Citation143^–^Citation146]
	EAC	Upregulation of PD-L1 in EAC is a favorable prognostic factor	Inhibition	[^Citation147]
Th17 cell	ESCC	IL-17A induced tumor cells to produce chemokines such as CCL20, CXCL-9, CXCL-10, and CXCL13, thereby recruiting effector T cells, DCs, B cells, and NK cells	Inhibition	[^Citation153,Citation154]
	ESCC	Th17 cell infiltration and amplification is promoted by chemokines such as CCL17, CCL20 and CCL22 and is associated with poor prognosis	Acceleration	[^Citation155,Citation156]
	EAC	IL-17A activates MMP-2 and MMP-9 through the ROS/NF-κB signaling pathway	Acceleration	[^Citation157]
Tregs	/	FOXP3 may play an immunosuppressive role by directly inhibiting the IL-2 gene or by promoting the expression of CTLA-4 and CD25	Acceleration	[^Citation158]
	ESCC	IL-33 promotes the expression of CCL2 through the NF-κB pathway, thereby recruiting Treg cells to promote tumor progression	Acceleration	[^Citation165,Citation166]
B cell	EAC	Breg cell interacts with Treg, MDSC, TAM and other immune cells to promote tumor growth	Acceleration	[^Citation168,Citation169]
NK cell	EC	Co-inhibitory receptor Tim-3 is highly expressed in NK cells and is associated with NK cell dysfunction	Acceleration	[^Citation174]
	ESCC	The co-cultured NK cells had a strong cytotoxic effect on ESCC cells expressing the NK cell activated receptor	Inhibition	[^Citation175]

Table 4 The Role of CAFs and ECM in the Tumor Microenvironment of Esophageal Cancer

Entry	Cancer Type	Finding	Effects on Tumors	Ref.
CAFs	ESCC	FAP+ CAFs-derived IL-6 promoted EMT and drug resistance, recruited FoxP3+ T cells, and induced M2 polarization of TAMs	Acceleration	[^Citation191^–^Citation194]
	ESCC	uPA secreted by CAFs promotes ESCC progression through the PI3K/AKT and ERK pathways	Acceleration	[^Citation195]
	EC	The high expression of Twist1 in CAFs promotes the secretion of CXCL12 and EMT through the ERK/AKT pathway	Acceleration	[^Citation196,Citation197]
	ESCC	HGF expressed by CAFs promotes progression and metastasis through the HGF/Met pathway	Acceleration	[^Citation198]
	ESCC	TGF-β1 expressed by CAFs promotes tumor progression through the TGF-β1/Smad pathway	Acceleration	[^Citation199,Citation200]
ECM	ESCC	Cancer cells can produce cancer-derived type I collagen with a molecular weight different from CAFs-derived collagen and inhibit tumor growth	Acceleration	[^Citation216]
	ESCC	High matrix FN environment promotes movement and migration of ESCC cells	Acceleration	[^Citation217]
	ESCC	TNC can also improve cancer stem cell properties and promote EMT-like changes through the Akt/HIF1α axis	Acceleration	[^Citation219]
	ESCC	High expression of ESCC cell gene ADAM12-L can promote FAK activation and promote cancer cell metastasis and migration through FAK/JNK/c-Jun axis	Acceleration	[^Citation220]
	ESCC	Increased expression of LOX, LOXL4 and 5-LOX is associated with poor prognosis	Acceleration	[^Citation223^–^Citation227]
	EAC	Elevated APE1 expression can induce ARF6 activity and up-regulate MMP-14, and up-regulation of MMP-14 can activate MMP-2 to mediate ECM degradation	Acceleration	[^Citation230,Citation231]

Figure 3 Immune landscape of immune cell interactions.

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