Table 1 PD-L2-regulatory network in tumour cells and immune system.

From: Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy

Regulation type	Effector	PD-L2 expression	Cancer/cell type	Regulation mechanism	Biological behaviour	Refs.
Genomic regulation	JAK2	Upregulation	Non-small cell lung cancer	The amplification of chromosome 9P24.1 increases PD-L2 through JAK2/STAT3 signaling.	Prevented histocompatibility complex class I antigen presentation pathway	[32, 92]
Epigenetic regulation (DNA methylation)	NA	Downregulation	Thyroid carcinoma, gliomas, colorectal cancer, melanoma, gastric adenocarcinomas	PD-L2 DNA promoter methylation decreases PD-L2 mRNA expression in tumour cells.	Promoted Crohn’s-like lymphoid reaction and overall lymphocytic reaction	[36, 37, 93, 94]
Epigenetic regulation (histone acetylation)	p300	Upregulation	Bone marrow dendritic cell	GM-CSF stimulated p300 combines with PU.1 to acetylate PD-L2 histone in DCs.	Suppressed DC-mediated immune response	[40]
	HDAC	Downregulation	Melanoma	HDAC deacetylates PD-L2 histone.	Decreased effectiveness of PD-1 immunotherapy	[41]
Transcriptional regulation	MYC, STAT3	Upregulation	Colon cancer, lung squamous carcinoma, macrophages	HSP90-mediated c-Myc and STAT3 bind with PD-L2 promoter to active transcription.	Stimulated T-cell-mediated tumour clearance	[43]
	BCL6, STAT1, STAT3, IRF1	Downregulation	B cell	BCL6 combines with the PD-L2 promoter to inhibit transcription and binds with STAT1, STAT3, and IRF1 promoters to inhibit transcription and damage their capability of activating PD-L2.	Sustained Tfh and Tfr cell-mediated humoral immunity	[46]
	STAT1, STAT3	Upregulation	Oral squamous cell carcinoma	Cisplatin‐induced STAT1, and STAT3 combine with the PD-L2 promoter.	Promoted proliferation and invasion of cisplatin-resistance	[48]
	STAT1, STAT3, c-FOS	Upregulation	Non-small cell lung cancer	IFN-γ-stimulated STAT1/3, c-FOS or EGFR and EML4-ALK activated STAT3, c-FOS combine with PD-L2 promoter.	Suppressed immune response	[47]
	STAT3	Upregulation	Macrophage	IL-27-stimulated STAT3 increases PD-L2 expression.	Increased tumour-associated macrophages mediated immune suppression microenvironment	[50]
	STAT3, NF-κB	Upregulation	γδT cell	JAK/STAT3 and TRIF/NF-κB axis promote PD-L2 expression and decrease IFN-γ, and TNF-α secretion.	Facilitated intrahepatic recurrence, dissemination and lung metastasis	[49]
	STAT3	Upregulation	Oral squamous cell carcinoma	VEGFR2 mediated STAT3 increasing PD-L2 expression.	Increased tumour migration and invasion	[51]
	STAT5, IRF4	Upregulation	Dendritic cell	STAT5b recruits EZH2 from the IRF4 promoter to the IRF8 promoter and increased IRF4 promotes PD-L2 expression.	Promoted DC-mediated immune response and limited autoimmune development	[40, 52]
	STAT5	Upregulation	Neutrophil	GM-CSF-stimulated STAT5 phosphorylation promotes PD-L2 expression in neutrophils to suppress T-cell proliferation.	Suppressed neutrophil-mediated immune response	[54]
	STAT5	Upregulation	B-1a cell	PD-L2 mediates STAT5 expression to decrease B-1a cell differentiation to ASC and IL-5 secretion in T cells.	Sustained humoral immunity	[53]
	STAT6	Upregulation	Macrophage	IL-4-activated IL-4Rα promote STAT6 that increase PD-L2 expression.	Suppressed macrophage-mediated immune response	[55]
	STAT6	Upregulation	Macrophage	IL-4/IL-13 activated STAT6 promotes PD-L2 expression to convert macrophage to AAM.	Suppressed macrophage-mediated immune response	[56]
	IRF4	Upregulation	Bone marrow dendritic cell	IRF4 combine with PD-L2 promoter with PU.1.	Suppressed DC-mediated immune response	[40]
	GATA2	Upregulation	Glioma	GATA2 combines with PD-L2 promoter region in neoantigen-specific T cells.	Suppressed T-cell-mediated immune response	[62]
	HOXC10	Upregulation	Glioma	HOXC10 combine with PD-L2 promoter.	Promoted proliferation, invasion, and immunosuppression of Glioma	[64]
	OCT2	Upregulation	B cell	OCT2 combine with PD-L2 promoter in B cells.	Suppressed T-cell-mediated immune response	[68]
	ETV4	Upregulation	Breast cancer	Integrin αvβ3 stimulated BRAF/TAK1/ERK axis active ETV4 to combine with PD-L1–L2-SE in breast cancer cells.	Suppressed T-cell-mediated immune response	[23]
Post-transcriptional regulation	PCED1B-AS1	Upregulation	Hepatocellular carcinoma	PCED1B-AS1 sponge hsa-mir-194-5p from PD-L2 mRNA to increase early apoptotic and decrease IL-2 secretion of T cells.	Suppressed immune response	[69]
	miR-BHRF1-2-5p	Downregulation	Diffuse large B-cell lymphoma	MiR-BHRF1-2-5p of EBV combines with PD-L2 mRNA 3’UTR to block PD-L2 expression.	EBV driving B-cell differentiation	[84]
Post-translational modification	FUT8	Upregulation	Head and neck squamous cell carcinoma	FUT8 promotes PD-L2 glycosylation to decrease ubiquitination degradation and increasing membrane expression.	Increased resistance of cetux monotherapy	[21]
Cell communication	LPS/CXCR3	Upregulation	Bone marrow dendritic cell	CXCR3 increase PD-L2 expression to activate DCs development and suppress antigen-specific T cell activation.	Suppressed DC-mediated immune response	[72]
	FCP/TLR4	Upregulation	Bone marrow dendritic cell	TLR4 in mast cells induced IL-13 promote PD-L2 expression in DCs to promote Th2 cell reactivity.	Sustained Th2 cell-mediated humoral immunity	[75]
	CCL2/CCR2	Upregulation	Oesophageal squamous cell carcinoma	The CCL2-CCR2 axis promotes PD-L2 expression in TAMs to increase TAM accumulation, and infiltration and deplete the antitumor effector of T cells.	Promoted immune infiltration and tumorigenesis	[73]
	IFN-α/ANO9	Upregulation	Gastric cancer	IFN-α induced ANO9 increase PD-L2 expression.	Promoted proliferation, migration, invasion, and mediating apoptosis	[74]
Others	GOLT1B	Upregulation	Colorectal cancer	GOLT1B combines with PD-L2 to increase membrane PD-L2 expression to increase apoptosis of T lymphocytes.	Promoted migration and immune escape	[28]
	MMP9, MMP13	Downregulation	Foreskin fibroblast	MMP9/13 combine with PD-L2 and hydrolyse PD-L2 to increase apoptosis of T cells.	Promoted T-cell-mediated immune response	[76]
	TLR9	Upregulation	Head and neck squamous cell carcinoma	HPV stimulated TLR9 increasing PD-L2 expression in fibroblasts and macrophages.	Suppressed immune response	[81]

OCT2 octamer binding protein 2, PD-L2 programmed death ligand-2, ETV4 ETS variant 4, BRAF v-RAF murine sarcoma viral oncogene homologue B1, TAK1 TGF-β-activated kinase 1, ERK extracellular signal-regulated kinase, PD-L1 L2-SE programmed death ligand-1/2 super-enhancer, APOBEC3 apolipoprotein B editing catalytic subunits protein 3, IFN-γ interferon-gamma, GM-CSF granulocyte–macrophage colony-stimulating factor, DC dendritic cell, PU.1 purine rich box-1, HDAC histone deacetylase, MYC MYC proto-oncogene, STAT3 signal transducer and activator of transcription 3, HSP90 heat shock protein 90, BCL6 B-cell lymphoma 6, STAT1 signal transducer and activator of transcription 1, IRF1 interferon regulatory factor-1, c-FOS c-fos proto-oncogene, EGFR epidermal growth factor receptor, EML4-ALK echinoderm microtubule-associated protein-like 4 gene-ALK variant, EGF epidermal growth factor, FUT8 fucosyltransferase 8, IL-27 interleukin 27, NF-κB nuclear factor-κB, JAK Janus kinase, TRIF TIR domain-containing adaptor inducing interferon-β, TNF-α tumour necrosis factor alpha, VEGFR2 vascular endothelial growth factor receptor-2, STAT5 signal transducer and activator of transcription 5, IRF4 interferon regulatory factor-4, STAT5b signal transducer and activator of transcription 5b, EZH2 enhancer of zeste homologue 2, IRF8 interferon regulatory factor-8, ASC apoptosis-associated speck-like protein containing CARD, IL-5 interleukin 5, STAT6 signal transducer and activator of transcription 6, IL-4 interleukin-4, IL-4Rα interleukin-4 receptor alpha, IL-13 interleukin 13, AAM alternatively activated macrophages, GATA2 hematopoietic transcription factor, IL-2 interleukin 2, HOXC10 homeodomain‑containing gene 10, PCED1B-AS1 lncRNA PC-esterase domain-containing 1B antisense RNA 1, EBV Epstein–Barr virus, MMP9 matrix metalloproteinase 9, MMP13 matrix metalloproteinase 13, ANO9 anoctamin 9, IFN-α interferon-alpha, GOLT1B Golgi vesicle transporter 1B, CXCR3 C-X-C motif chemokine receptor 3, CCL2 C-C motif chemokine ligand-2, CCR2 C-C motif chemokine receptor-2, TAM tumour-associated macrophages, TLR4 Toll-like receptor 4, IL-13 interleukin 5, TLR9 Toll-like receptor 9, HPV human papillomavirus.

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Table 1 PD-L2-regulatory network in tumour cells and immune system.

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