Comprehensive insights into the effects and regulatory mechanisms of immune cells expressing programmed death-1/programmed death ligand 1 in solid tumors

Min Liu; Qian Sun; Feng Wei; Xiubao Ren

doi:10.20892/j.issn.2095-3941.2020.0112

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Figure 1
Mechanism by which PD-1/PD-L1 expression on immune cells is regulated. (A) In T cells, under TCR-mediated stimulation, NFAT drives the effector gene and PD-1 expression after association with the CD28 signaling-activated AP-1 complex. Common γ-chain family cytokines directly induce PD-1 expression and enhance the induction and maintenance of TCR-mediated PD-1 expression. The Notch signaling pathway affects PD-1 transcription by forming a complex on the PD-1 promoter. The fucosylation pathway is a positive regulator of PD-1 expression. In contrast, Blimp-1 directly binds to the PD-1 gene to inhibit NFATc1 expression or to form an inhibitory chromatin structure that inhibits PD-1 expression. DNA methylation and aerobic glycolysis are inversely related to PD-1 expression. For PD-L1, the presentation of tumor antigens and inflammatory signals induces PD-L1 expression. (B) In B cells, TLR4-mediated BCL6 upregulation is crucial for PD-1 expression. Notably, IL-4-induced STAT6 activation completely eliminates BCL6-mediated PD-1 upregulation. HCC-SN and circulating exosomes induce differentiation of PD-1^hi Bregs. PD-L1 expression on B cells is due to membrane-bound PD-L1 in MDSC-derived microvesicles. (C) In DCs, PD-1 is induced on DCs by various inflammatory stimuli. TGF-β increases the expression of PD-L1 by TGF-β-STAT3-PD-L1 signaling. Exposure to oxaliplatin significantly increases expression of PD-L1. However, apigenin limits PD-L1 expression in DCs. (D) In macrophages, miR-23a-3p upregulates the expression of PD-L1 by regulating the PTEN-AKT pathway. ROS activate the NF-κB signaling pathway, thereby promoting PD-L1 transcription. IFN-γ and its receptor bind to JAK, leading to STAT phosphorylation and translocation into the nucleus to regulate PD-L1 expression. TLR4-mediated MyD88-p38-STAT3 signaling stimulates PD-L1 expression. TNF-α, IL-10, and HIF-1α stimulate PD-L1 expression. (E) In granulocytes, tumor-derived GM-CSF induces PD-L1 expression via the JAK/STAT3 signaling pathway. IRAK-M-deficient neutrophils inhibit PD-L1 expression by reducing the activation of STAT1/3 and enhancing the activation of STAT5. Tumor-derived TNF-α induces PD-L1 expression on mast cells by activating the NF-κB signaling pathway. Tollip in neutrophils results in decreased PD-L1 expression. (F) In MDSCs, IFN-γ activates the expression of IRF1, and IRF1 binds to the unique IRF-binding consensus sequence element of CD274 promoter chromatin to directly activate PD-L1 expression. Extracellular vesicles upregulate the expression of PD-L1 in a Toll-like signaling-dependent manner. HIF-1α also stimulates the expression of PD-L1, but respiratory hyperoxia treatment inhibits the expression of PD-L1. Programmed cell death-1, PD-1; programmed cell death ligand 1, PD-L1; nuclear factor of activated T cells, NFAT; T cell receptor, TCR; activating protein-1, AP-1; interferon, IFN; interleukin 2, IL-2; interferon regulatory factor 9, IRF9; signal transducer and activator of transcription6, STAT6; Notch1 intracellular domain, NICD; recombination signal binding protein for immunoglobulin kappa J region, RBPJK; Culture supernatant from primary HCC tumor cells, HCC-SN; Toll-like receptor-4, TLR-4; B-cell lymphoma 6, BCL6; tumor necrosis factor-α, TNF-α; granulocyte-macrophage colony-stimulating factor, GM-CSF; reactive oxygen species, ROS; nuclear factor kappa B, NF-κb; myeloid differentiation primary response gene 88, MyD88; hypoxia-inducible factor-1α, HIF-1α; Janus kinase, JAK; IL-1 receptor-associated kinase M, IRAK-M.

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Table 1

Characteristics of immune cells expressing PD-1/PD-L1 in tumors immunity

Cell types	Phenotypes	Target cells	Effects	Cancer types	References
T cells	PD-1⁺CD8⁺ T cell	Tumor cells	Induce T cell exhaustion	Liver, pancreatic, HNC, NSCLC, early breast cancer	^9–12
	PD-L1⁺ T cell	Neighboring effector T cells, macrophages	Promote STAT6-dependent M2-like macrophage differentiation and suppress neighboring effector T cells	Pancreatic ductal adenocarcinoma	³²
B cells	PD-1^hiCD5^hiCD24^-/+CD27^hi/+CD38^dim B cell	T cells	T-cell dysfunction and foster disease progression	Hepatoma	¹⁴
	PD-1⁺ B cell	CD4⁺ and CD8⁺ T cells	Inhibit CD4⁺ and CD8⁺ T cell proliferation	Thyroid tumors	³³
	PD-L1^hi B cell, PD-1^-PD-L1⁺CD19⁺, PD-L1⁺CD24⁺CD38⁺CD19⁺ B cell	T cells	Inhibit T cell proliferation and promote the formation of Tregs	Breast cancer	^34–37
	PD-L1⁺CD155⁺IL-10⁺TGF-β⁺ B cell	CD8⁺ T cells	Inhibit CD8⁺ T cell proliferation, IFN-γ production, and expression of the granzyme B	GBM	³⁸
	PD-L1⁺IgA⁺IL-10-producing Plasmocyte	CD8⁺ T cells, CTLs	Induce CD8⁺ T cell depletion and inhibit the immune response of CTLs	Prostate tumors	³⁹
	PD-L1⁺IgA⁺IL-10⁺ Plasma cell	CD8⁺ T cells	Inhibit activation of CTLs	Hepatocellular carcinoma	³³
	PD-L1⁺IgA⁺CD19⁺ B cell	CD8⁺ T cells	Inhibit the proliferation and activation of CD8⁺ T cells	Colorectal cancer	⁴⁰
NK cells	PD-1⁺NKG2A^-KIR⁺CD57⁺ NK cell	Tumor cells	Low proliferative response of NK cells and impaire antitumor activity	Ovarian cancer, colorectal cancer, gastric cancer, ESCC, HCC, biliary cancer, melanoma	^17,44–46
DCs	PD-1⁺CD11c⁺ DC	CD8⁺ T cells	Inhibit the secretion of perforin and granzyme B by CD8⁺ T cells	HCC	⁴⁸
	PD-1⁺PD-L1⁺CD11c⁺CD8α^-Gr-1^{lo / int} DC	T cells, DC cells	Inhibit T cell proliferation, regulate cytokine production by DCs and maintain their immature phenotype	Ovarian cancer	¹⁹
	PD-L1⁺ DC	CIK cells	Reduce the ability of DC-CIK-mediated melanoma cell killing assays	Melanoma	⁵¹
	PD-L1⁺ DC	T cells	Induce the apoptosis of T cells and increase the percentage of Tregs	HCC	⁶²
Mononuclear macrophages	PD-1⁺CD11c⁺MHC-II⁺ CD4⁺CD68⁺ TAM	Tumor cells	Decreased phagocytosis	Colorectal cancer	²⁰
	PD-1⁺ Macrophage	Tumor cells	Weaken the cytotoxic effect on mesothelioma cells	Malignant pleural mesothelioma	⁵²
	PD-L1⁺HLA-DR^highCD68⁺ Macrophage	T cells	Induce T cell anergy and reduce IFN-γ production by T cells	HCC	²¹
	PD-L1⁺ CD68⁺ Macrophage	T cells	Decrease the proportion of CD8⁺ T cells and promote T cell apoptosis	HCC	⁵³
	PD-L1⁺F4/80⁺ Macrophage	CD8⁺ T cells	Reduce the number of activated T lymphocytes	Bladder cancer	⁵⁴
	PD-L1⁺CD11b⁺F4/80⁺ Macrophage	CD4⁺ and CD8⁺ T cells	Inhibit CD4⁺ and CD8⁺ T cell proliferation	Melanoma	⁵⁵
	PD-L1⁺CD45⁺CD11b⁺ Macrophage	T cells	Induce T cell apoptosis	Glioma	⁶³
	PD-L1⁺CD11b⁺F4/80⁺ TAM CD169⁺ Macrophage	T cell	Inhibit T cell-mediated antitumor response	TNBC	^64,65
	PD-L1⁺CXCL8⁺CD68⁺CD45⁺ Macrophage	CD8⁺ T cells	Inhibit CD8⁺ T cells function	Gastric cancer	⁵⁶
	PD-L1⁺HLA-Dr^hiCD14⁺ TAM	T cells	Protect TAMs from being killed by cognate effector T cells	Early-stage lung tumor	⁵⁷
Granulocytes	PD-L1⁺CD45⁺CD117⁺Fc?RI⁺ Mast cell	T cells	Inhibit normal T cell immunity	Gastric cancer	²⁵
	PD-L1⁺CXCL5⁺CXCR4⁺ CCR5⁺Adam1⁺Nos2⁺Neutrophil	T cells	Immunosuppressive effects in T cell proliferation	Cutaneous melanoma	⁵⁹
	PD-L1⁺ CD54⁺ Neutrophil	T cells	Suppresse normal T-cell immunity	Gastric cancer	²⁴
	PD-L1⁺Tollip⁺ Neutrophil	T cells	Reduce T cell activation, suppress tumor immune surveillance and increase the tumor burden	Colorectal cancer	⁶⁶
	PD-L1^hiCD11b^hiCD80^lowIRAK-M⁺ Neutrophil	T cells	Inhibit T cell activation	Colitis-associated tumor	⁶⁷
MDSCs	PD-L1⁺Gr-1⁺CD11b⁺ MDSC	MDSCs, T cells	Increase MDSC-mediated T cell suppression, increased IL-10 and IL-6 secretion of MDSC and inhibited IFN-γ production of T cells	Mammary carcinoma, LLC, melanoma, colon carcinoma	²⁷
	PD-L1⁺Gr-1⁺CD11b⁺ MDSC	T cells	Inhibit T cell activation	Melanoma	⁶¹