Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Zhang, Hao; Dai, Ziyu; Wu, Wantao; Wang, Zeyu; Zhang, Nan; Zhang, Liyang; Zeng, Wen-Jing; Liu, Zhixiong; Cheng, Quan

doi:10.1186/s13046-021-01987-7

Journal of Experimental & Clinical Cancer Research

Table 1 Regulators of PD-L1

From: Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Regulatory Types	Regulators		PD-L1	Cancer types		References
Regulation of PD-L1 at DNA level	Genomic alteration	amplifications		Upregulation	Hodgkin’s lymphoma, SCLC, NSCLC, EBV-positive gastric cancer, and squamous cell carcinoma of the oral cavity.	[20,21,22,23, 25, 26]
	Genomic alteration	translocations		Upregulation	mediastinal large B cell lymphoma	[24]
	Epigenetic regulation	histone deacetylases	HDAC3	Upregulation	drug-resistant cancer	[27]
		histone deacetylases	HDAC6	Upregulation	melanoma	[28]
		methylation of DNA at CpG sites		Downregulation	melanoma, NSCLC, HNSCC, and CRC	[29,30,31,32]
		H3K4me3		Upregulation	pancreatic cancer and breast cancer	[33, 34]
		H3K27me3		Downregulation	HCC	[35]
Regulation of PD-L1 at RNA level	Inflammatory signaling	IFN-γ		Upregulation	sarcoma, colon cancer, melanoma, and NSCLC	[36,37,38]
		IFN-α, IFN-β		Upregulation	melanoma	[39]
		TLR4		Upregulation	bladder cancer	[40, 41]
		TLR3		Upregulation	neuroblastoma	[42]
		IL-17		Upregulation	prostate cancer and colon cancer	[43]
		IL-4		Upregulation	RCC	[44]
		IL-27		Upregulation	ovarian cancer; Prostate cancer; NSCLC	[45]
		IL-6		Upregulation	prostate cancer; HCC; GBM; NSCLC	[46,47,48,49]
		IL-10		Upregulation	OSCC	[50]
		TGF-β		Upregulation	NSCLC	[51, 52]
	Aberrant oncogenic signaling	EGFR			NSCLC and LUAD	[53, 54]
		ERK			multiple myeloma, breast cancer, NSCLC, bladder cancer, pancreatic cancer, and lymphoma	[55,56,57,58,59,60]
		PTEN		Downregulation	breast cancer	[58, 61,62,63,64,65,66,67,68,69]
		PTEN/PI3K/AKT		Upregulation	gastric cancer, NSCLC, CRC, glioma, melanoma, HNSCC, CRC, and Her2- amplified cancer	[70]
		JAK-STAT		Upregulation	breast cancer and NSCLC	[23, 71, 72]
		NF-κB		Upregulation	NSCLC, breast cancer, melanoma	[73,74,75,76,77]
		HIF-1		Upregulation	LUAD, RCC	[78,79,80,81,82,83,84]
		MYC		Upregulation	melanoma, NSCLC, ESCC, leukemia, lymphoma, and pancreatic cancer	[85,86,87,88,89,90,91,92]
		MYC		Downregulation	HCC	[93]
		ALK		Upregulation	NSCLC, lymphoma, LUAD	[79, 94,95,96,97]
		Met		Upregulation	NSCLC	[98,99,100]
		BRD4		Upregulation	ovarian cancer, lymphoma	[101, 102]
		DSB		Upregulation	osteosarcoma, NSCLC, and prostate cancer	[103]
		AP-1		Upregulation	Hodgkin’s lymphoma	[104, 105]
		SHH		Upregulation	gastric cancer	[106]
		P53		Upregulation	melanoma, NSCLC, mesothelioma, GBM	[107,108,109,110]
	Epigenetic regulation	N6-methyladenosine (m6A) methylation		Downregulation	HNSCC, LUAD, and colon cancer	[111,112,113,114]
	Direct regulation by miRNA	miR-34a		Downregulation	AML and lymphoma	[115, 116]
		miR-142-5p		Downregulation	pancreatic cancer	[117]
		miR-93, miR-106b		Downregulation	pancreatic cancer	[118]
		miR-138-5p		Downregulation	CRC	[119]
		miR-217		Downregulation	laryngeal cancer	[120]
		miR-200		Downregulation	NSCLC and gastric cancer	[121, 122]
		miR-152		Downregulation	gastric cancer	[122]
		miR-570		Downregulation	gastric cancer	[123]
		miR-17-5p		Downregulation	melanoma	[124]
		miR-15a, miR-193a, miR-16		Downregulation	malignant pleural mesothelioma	[125]
		miR-148a-3p		Downregulation	CRC	[126]
		miR-873		Downregulation	breast cancer	[127]
		miR-424(322)		Downregulation	ovarian cancer	[128]
		miR-214		Downregulation	lymphoma	[129]
		miR-497-5p		Downregulation	RCC	[130]
		miR-140		Downregulation	NSCLC	[131]
	Indirect regulation by miRNA	miR-20, miR-21, miR-130b		Upregulation	CRC	[132]
		miR-23a-3p		Upregulation	HCC	[133]
		miR-18a		Upregulation	cervical cancer	[134]
		miR-197		Downregulation	NSCLC	[135]
		miR-145		Downregulation	ovarian cancer	[136]
	mRNA stablization	RAS		Upregulation	RAS mutant cancer	[137]
		Angiotensin II		Upregulation	NSCLC	[138]
		G3BP2		Upregulation	breast cancer and GBM	[139]
Regulation of PD-L1 at protein level	Ubiquitination	c-Cbl and Cbl-b		Downregulation	NSCLC	[140]
		USP22		Upregulation	HCC	[141]
		USP9X		Upregulation	OSCC	[142]
		UCHL1		Upregulation	NSCLC	[143]
		CMTM6		Downregulation	melanoma, NSCLC, CRC, thyroid cancer, pancreatic cancer, breast cancer	[144, 145]
		CMTM4		Downregulation	NSCLC and melanoma	[145]
		CDK4		Downregulation	cervical cancer and breast cancer	[146]
		CSN5		Downregulation	breast cancer	[147]
	Phosphorylation	Tyr112		Upregulation	HCC	[148]
		S195		Downregulation	breast cancer	[149]
		GSK3β		Downregulation	breast cancer	[150, 151]
	Glycosylation	N192/200/219		Upregulation	breast cancer	[150]
		STT3		Upregulation	cancer stem cell	[152]
		FKBP51s		Upregulation	glioma	[153]
	Palmitoylation	C272		Upregulation	breast cancer and colon cancer	[154, 155]
Extracellular PD-L1	exosome			Upregulation	HNSCC, breast cancer, and melanoma	[156,157,158,159]
Extracellular PD-L1	soluble protein			Upregulation	NSCLC	[160,161,162,163]
Biomarkers	TMB			Upregulation	multiple cancer types	[164]
	MSI			Upregulation	multiple cancer types	[165]
	TIL			Upregulation	multiple cancer types	[166]
	Intratumor heterogeneity			Upregulation	multiple cancer types	[167]

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ISSN: 1756-9966

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