Role of immune escape in different digestive tumours

Table 1 The mechanisms of immune escape in different digestive tumours

Molecules/cells	Ref.	Tumor/cancer	Cells/cytokines	Up/down	Pathway/target	Outcomes
HLA-G	Bespalova et al[8], 2020; Liu et al[16], 2020	CRC	NK cells, T lymphocytes, and antigen-presenting cells	Up	ILT-2, ILt-4, and KIR2DL4	By directly binding to the inhibitory receptors ILT-2, ILt-4, and KIR2DL4, leading to apoptosis of NK and T cells and weakening host immune defences
HLA-I	Zhao et al[11], 2011; Li et al[12], 2010; Özgül Özdemir et al[19], 2016	Oesophageal malignant tumour, CRC	CD8+ T cells, T lymphocytes	Down	TAA	Downregulates the expression of HLA-I and reduces the expression of tumour-associated antigen (TAA) on the surface of tumour cells, evading recognition and attack by immune cells
HLA-E	Huang et al[17], 2017; Abd Hamid et al[18], 2019	Early CRC	CTLs and NK cells	Up	CD94/NKG2A	HLA-E is overexpressed on the surface of early CRC cells and can bind to the HLA-E receptor CD94/NKG2A, which is expressed on the surface of CTLs and NK cells, thus inhibiting their activity
PD-L1	Calderaro et al[27], 2016	Oesophageal carcinoma	EGFR	Up	PI3K/AKT, EGFR-RAS-RAF-ERK	Binding of the transmembrane protein - programmed death-ligand 1 (PD-L1) expressed in tumour cells or cells in the TME to PD-1 expressed on T cells can induce the production of immunosuppressive signals and decrease the proliferation of T cells, resulting in the depletion of T cells
	Liu et al[30], 2020	CRC	CCL5	Up	p65/STAT3-CSN5-PD-L1	Stabilizes PD-L1 in and out of cells through the p65/STAT3-CSN5-PD-L1 pathway mediated by NF-κB1 p65 (p65), which inhibits T-cell-mediated killing of HT29 tumour cells
	Ghedini et al[31], 2018	CRC	FGFR2	Up	JAK/STAT3	The tyrosine kinase domain initiates a series of intracellular signal cascade reactions, activates the JAK/STAT3 signalling pathway, and induces PD-L1 expression in CRC cells, thus participating in the occurrence and development of CRC
	Li et al[34], 2019	CRC	CXCL5	Up	PIK3/Akt	The binding of CXCL5 to CXCR2 on the surface of CRC cells promotes the movement of the CXCL5-CXCR2 axis, thus activating the PI3K/AKT signalling pathway and upregulating the expression of PD-L1 in CRC
	Li et al[38], 2019	Gallbladder malignant tumour	T cells	Up	PIK3/Akt	Upregulation of PD-L1 in gallbladder malignant tumour cells, activated the PIK3/Akt pathway, inhibited the cytotoxicity mediated by normal T cells, and promoted tumour growth and development
Galectin-9	Wang et al[41], 2016; Halama et al[43], 2011	Oesophageal carcinoma, CRC	NK cells	Down	Rho/ROCK-1, F-actin polarization	The low expression of Galectin-9 may lead to decreased activation or insufficient transport of NK cells to the tumour site
DKK2	Xiao et al[44], 2018	CRC	NK cells, CD8+ T cells	Up	STAT	The binding of DKK2 to LRP5 on the surface of NK cells leads to the disordering of STAT5 nuclear localization in NK cells and hinders the activation of NK cells
MDSCs	Geiger et al[53], 2016	CRC	T cells	Up	L-arginine	The high expression of MDSCs consumes a large quantity of L-arginine, and the resulting depletion of L-arginine affects T-cell proliferation
	Li et al[54], 2018	Oesophageal carcinoma	T cells	Up	Akt1/rela/IL8	Oesophageal malignant tumour cells can guide MDSCs to migrate to the tumour site and promote tumour progression by activating the Akt1/rela/IL8 signalling pathway
Treg cells	Chen et al[60], 2017	CRC	TCR	Up	CXCL13-CXCR5 axis	HDCC mainly promotes the infiltration of Treg cells by binding to CXCR5 on the surface of Treg cells by secreting CXCL13, which initiates the CXCL13-CXCR5 axis, promotes the proliferation of Treg cells and the aggregation of Treg cells at the tumour site
TIM-3	Shan et al[72], 2016	Oesophageal carcinoma	CD4+ Th1, CD8+ T cells, dysfunctional CD8+ T cells and FoxP3+ Treg cells	Up	AKT/GSK-3 β/Snail	A high expression of TIM-3 in tumour cells often indicates a poor prognosis of tumours
CD47	Fujiwara-Tani et al[76], 2019	Gastric tumour, CRC	Macrophages	Up	Sirp α	CD47 can prevent macrophage-mediated phagocytosis and antigen presentation by interacting with the receptor Sirp α expressed on macrophages, thus allowing tumour cells to escape the immune surveillance of macrophages
NF-κB	Ouyang et al[83], 2021; He et al[84], 2021	Gallbladder malignant tumours, Pancreatic malignant tumours, CRC	T cell granzyme B gene	Up	Toll-like receptor 4, NF- κB/p65	NF-κB realizes the immune escape of tumour cells by affecting the transcription of effector T cells at the cellular transcriptional level. NF-κB inhibits GZMB transcription in T cells, induces CTL dysfunction, and promotes tumour immune escape
IDO1+ Paneth cells	Mezrich et al[90], 2010	Oesophageal carcinoma, CRC	CD8+ T cells	Up	Canine uric acid, tryptophan	IDO facilitates immune escape by locally increasing the level of canine uric acid derived from tumour epithelial cells and consuming tryptophan. The increased level of canine uric acid promotes the differentiation of Treg cells through the aromatic hydrocarbon receptor AhR29, and the depletion of tryptophan can lead to cell cycle arrest of T cells, both of which can inhibit the antitumour immune response