Abstract
Immune checkpoint molecules, including inhibitory and stimulatory immune checkpoint molecules, are defined as ligand–receptor pairs that exert inhibitory or stimulatory effects on immune responses. Most of the immune checkpoint molecules that have been described so far are expressed on cells of the adaptive immune system, particularly on T cells, and of the innate immune system. They are crucial for maintaining the self-tolerance and modulating the length and magnitude of immune responses of effectors in different tissues to minimize the tissue damage. More and more evidences have shown that inhibitory or stimulatory immune checkpoint molecules are expressed on a sizeable fraction of tumor types. Although the main function of tumor cell-associated immune checkpoint molecules is considered to mediate the immune evasion, it has been reported that the immune checkpoint molecules expressed on tumor cells also play important roles in the maintenance of many malignant behaviors, including self-renewal, epithelial–mesenchymal transition, metastasis, drug resistance, anti-apoptosis, angiogenesis, or enhanced energy metabolisms. In this section, we mainly focus on delineating the roles of the tumor cell-associated immune checkpoint molecules beyond immune evasion, such as PD-L1, PD-1, B7-H3, B7-H4, LILRB1, LILRB2, TIM3, CD47, CD137, and CD70.
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References
Alsuliman A et al (2015) Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol Cancer 14:149
Anderson AC et al (2007) Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318(5853):1141–1143
Baccelli I et al (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31(6):539–544
Bachawal SV et al (2015) Breast Cancer Detection by B7-H3-Targeted Ultrasound Molecular Imaging. Cancer Res 75(12):2501–2509
Baudhuin J et al (2013) Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions. Proc Natl Acad Sci U S A 110(44):17957–17962
Black M et al (2016) Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget 7(9):10557–10567
Borges L et al (1997) A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol 159(11):5192–5196
Bras M et al (2007) Drp1 mediates caspase-independent type III cell death in normal and leukemic cells. Mol Cell Biol 27(20):7073–7088
Brown E et al (1990) Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins. J Cell Biol 111(6 Pt 1):2785–2794
Butte MJ et al (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27(1):111–122
Cao Y et al (2011) B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Res 71(4):1235–1243
Cao D et al (2019) Retinoic acid-related orphan receptor C regulates proliferation, glycolysis, and chemoresistance via the PD-L1/ITGB6/STAT3 signaling axis in bladder cancer. Cancer Res 79(10):2604–2618
Carbone C et al (2015) An angiopoietin-like protein 2 autocrine signaling promotes EMT during pancreatic ductal carcinogenesis. Oncotarget 6(15):13822–13834
Chan KS et al (2009) Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A 106(33):14016–14021
Chang CH et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6):1229–1241
Chao MP et al (2010) Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142(5):699–713
Chao MP et al (2011) Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res 71(4):1374–1384
Chapoval AI et al (2001) B7-H3: A costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2(3):269–74
Chen L, Han X (2015) Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 125(9):3384–3391
Chen YW, Tekle C, Fodstad O (2008) The immunoregulatory protein human B7H3 is a tumor-associated antigen that regulates tumor cell migration and invasion. Curr Cancer Drug Targets 8(5):404–413
Chen DS, Irving BA, Hodi FS (2012) Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 18(24):6580–6587
Chen X et al (2016) B7-H4 facilitates proliferation of esophageal squamous cell carcinoma cells through promoting interleukin-6/signal transducer and activator of transcription 3 pathway activation. Cancer Sci 107(7):944–954
Cheng L et al (2009) B7-H4 expression promotes tumorigenesis in ovarian cancer. Int J Gynecol Cancer 19(9):1481–1486
Chu DT et al (2019) An update on Anti-CD137 antibodies in immunotherapies for cancer. Int J Mol Sci 20(8)
Cioffi M et al (2015) Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin Cancer Res 21(10):2325–2337
Colonna M, Nakajima H, Cella M (2000) A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin Immunol 12(2):121–127
Colovai AI et al (2007) Expression of inhibitory receptor ILT3 on neoplastic B cells is associated with lymphoid tissue involvement in chronic lymphocytic leukemia. Cytometry B Clin Cytom 72(5):354–362
Cortesini R (2007) Pancreas cancer and the role of soluble immunoglobulin-like transcript 3 (ILT3). JOP 8(6):697–703
Croft M (2009) The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9(4):271–285
de Goeje PL et al (2015) Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer. Oncoimmunology 4(7):e1014242
Deng M et al (2018) LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 562(7728):605–609
Denoeud J, Moser M (2011) Role of CD27/CD70 pathway of activation in immunity and tolerance. J Leukoc Biol 89(2):195–203
Dharmadhikari B et al (2016) CD137 and CD137L signals are main drivers of type 1, cell-mediated immune responses. Oncoimmunology 5(4):e1113367
Dong H et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800
Du W et al (2017) TIM-3 as a target for cancer immunotherapy and mechanisms of action. Int J Mol Sci 18(3)
Fan H, Zhu JH, Yao XQ (2016) Prognostic significance of B7-H3 expression in patients with colorectal cancer: A meta-analysis. Pak J Med Sci 32(6):1568–1573
Feng ZM, Guo SM (2016) Tim-3 facilitates osteosarcoma proliferation and metastasis through the NF-kappaB pathway and epithelial-mesenchymal transition. Genet Mol Res 15(3)
Feng J et al (2017) Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 36(42):5829–5839
Flies DB et al (2014) Coinhibitory receptor PD-1H preferentially suppresses CD4(+) T cell-mediated immunity. J Clin Invest 124(5):1966–1975
Gao A, Sun Y, Peng G (2018) ILT4 functions as a potential checkpoint molecule for tumor immunotherapy. Biochim Biophys Acta Rev Cancer 1869(2):278–285
Ge H et al (2017) Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM. Int J Cancer 141(7):1434–1444
Ghebeh H et al (2007) Expression of B7-H1 in breast cancer patients is strongly associated with high proliferative Ki-67-expressing tumor cells. Int J Cancer 121(4):751–758
Goto H et al (2014) Efficacy of anti-CD47 antibody-mediated phagocytosis with macrophages against primary effusion lymphoma. Eur J Cancer 50(10):1836–1846
Grivennikov SI, Karin M (2010) Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21(1):11–19
Harly C et al (2011) Up-regulation of cytolytic functions of human Vdelta2-gamma T lymphocytes through engagement of ILT2 expressed by tumor target cells. Blood 117(10):2864–2873
Hastings WD et al (2009) TIM-3 is expressed on activated human CD4 + T cells and regulates Th1 and Th17 cytokines. Eur J Immunol 39(9):2492–2501
Heidenreich S et al (2012) Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma. Clin Dev Immunol 2012:652130
Isenberg JS et al (2006) CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1. J Biol Chem 281(36):26069–26080
Ishibashi M et al (2016) Myeloma drug resistance induced by binding of myeloma B7-H1 (PD-L1) to PD-1. Cancer Immunol Res 4(9):779–788
Jacobs J et al (2015) CD70: an emerging target in cancer immunotherapy. Pharmacol Ther 155:1–10
Jaiswal S et al (2009) CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138(2):271–285
Jaiswal S et al (2010) Macrophages as mediators of tumor immunosurveillance. Trends Immunol 31(6):212–219
Jan M et al (2011) Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci U S A 108(12):5009–5014
Jeon YK et al (2015) Cancer cell-associated cytoplasmic B7-H4 is induced by hypoxia through hypoxia-inducible factor-1alpha and promotes cancer cell proliferation. Biochem Biophys Res Commun 459(2):277–283
Jeong H et al (2019) Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis. Cancer Res 79(4):795–806
Jiang B et al (2016) The co-stimulatory molecule B7-H3 promotes the epithelial-mesenchymal transition in colorectal cancer. Oncotarget 7(22):31755–31771
Jiang P et al (2019) CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages. Theranostics 9(10):2950–2966
Jin L et al (2018) CD70, a novel target of CAR T-cell therapy for gliomas. Neuro Oncol 20(1):55–65
Kang X et al (2015) The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. Nat Cell Biol 17(5):665–677
Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092):431–436
Katz HR (2006) Inhibition of inflammatory responses by leukocyte Ig-like receptors. Adv Immunol 91:251–272
Kaur S, Roberts DD (2011) CD47 applies the brakes to angiogenesis via vascular endothelial growth factor receptor-2. Cell Cycle 10(1):10–12
Kaur S et al (2016) A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer. Oncotarget 7(9):10133–10152
Keir ME et al (2008) PD-1 and its ligands in tolerance and immunity. Ann Rev Immunol 26:677–704
Kikushige Y et al (2010) TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 7(6):708–717
Kikushige Y et al (2015) A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell 17(3):341–352
Kim JO et al (2003) NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells. FEBS Lett 541(1–3):163–170
Kim MJ et al (2008) Association of CD47 with natural killer cell-mediated cytotoxicity of head-and-neck squamous cell carcinoma lines. Tumour Biol 29(1):28–34
Kim JD, Kim CH, Kwon BS (2011) Regulation of mouse 4-1BB expression: multiple promoter usages and a splice variant. Mol Cells 31(2):141–149
Kim T et al (2013) Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341(6152):1399–1404
Kim HK et al (2014) B7-H4 downregulation induces mitochondrial dysfunction and enhances doxorubicin sensitivity via the cAMP/CREB/PGC1-alpha signaling pathway in HeLa cells. Pflugers Arch 466(12):2323–2338
Kleffel S et al (2015) Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell 162(6):1242–1256
Kortylewski M, Jove R, Yu H (2005) Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 24(2):315–327
Krambeck AE et al (2006) B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc Natl Acad Sci U S A 103(27):10391–10396
Kwon BS, Weissman SM (1989) cDNA sequences of two inducible T-cell genes. Proc Natl Acad Sci U S A 86(6):1963–1967
Lee TK et al (2014) Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60(1):179–191
Li Y et al (2017a) B7-H3 promotes gastric cancer cell migration and invasion. Oncotarget 8(42):71725–71735
Li Y et al (2017b) B7-H3 promotes the proliferation, migration and invasiveness of cervical cancer cells and is an indicator of poor prognosis. Oncol Rep 38(2):1043–1050
Li Y et al (2017c) Overexpression of CD47 predicts poor prognosis and promotes cancer cell invasion in high-grade serous ovarian carcinoma. Am J Transl Res 9(6):2901–2910
Lim S et al (2016) Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1alpha. Cancer Res 76(8):2231–2242
Lindberg FP et al (1993) Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding. J Cell Biol 123(2):485–496
Lindberg FP et al (1996) Integrin-associated protein immunoglobulin domain is necessary for efficient vitronectin bead binding. J Cell Biol 134(5):1313–1322
Liu J et al (2014) Inhibitory receptor immunoglobulin-like transcript 4 was highly expressed in primary ductal and lobular breast cancer and significantly correlated with IL-10. Diagn Pathol 9:85
Liu X et al (2015) ANGPTL2/LILRB2 signaling promotes the propagation of lung cancer cells. Oncotarget 6(25):21004–21015
Liu S et al (2017a) PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways. Oncotarget 8(59):99901–99912
Liu L et al (2017b) Anti-CD47 antibody as a targeted therapeutic agent for human lung cancer and cancer stem cells. Front Immunol 8:404
Luo D et al (2017) B7-H3 regulates lipid metabolism of lung cancer through SREBP1-mediated expression of FASN. Biochem Biophys Res Commun 482(4):1246–1251
Ma G et al (2011) Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells. Immunity 34(3):385–395
Majeti R et al (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138(2):286–299
Manna PP, Frazier WA (2004) CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A. Cancer Res 64(3):1026–1036
Marimpietri D et al (2013) Proteome profiling of neuroblastoma-derived exosomes reveal the expression of proteins potentially involved in tumor progression. PLoS ONE 8(9):e75054
Mateo V et al (1999) CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia. Nat Med 5(11):1277–1284
Mateo V et al (2002) Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization. Blood 100(8):2882–2890
Matozaki T et al (2009) Functions and molecular mechanisms of the CD47-SIRPalpha signalling pathway. Trends Cell Biol 19(2):72–80
Monney L et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415(6871):536–541
Mori Y et al (2008) Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development. J Immunol 181(7):4742–4751
Naji A et al (2012) Neoplastic B-cell growth is impaired by HLA-G/ILT2 interaction. Leukemia 26(8):1889–1892
Nakaima Y et al (2013) CD137 is induced by the CD40 signal on chronic lymphocytic leukemia B cells and transduces the survival signal via NF-kappaB activation. PLoS ONE 8(5):e64425
Ni L, Dong C (2017) New B7 family checkpoints in human cancers. Mol Cancer Ther 16(7):1203–1211
Nunes-Xavier CE et al (2016) Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors. Oncotarget 7(6):6891–6901
Palazon A et al (2012) The HIF-1alpha hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. Cancer Discov 2(7):608–623
Palma C et al (2004) CD137 and CD137 ligand constitutively coexpressed on human T and B leukemia cells signal proliferation and survival. Int J Cancer 108(3):390–398
Palsson-McDermott EM et al (2017) Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors. Front Immunol 8:1300
Park YP et al (2018) CD70 as a target for chimeric antigen receptor T cells in head and neck squamous cell carcinoma. Oral Oncol 78:145–150
Pich C et al (2016) Melanoma-expressed CD70 is involved in invasion and metastasis. Br J Cancer 114(1):63–70
Pizon M et al (2018) B7-H3 on circulating epithelial tumor cells correlates with the proliferation marker, Ki-67, and may be associated with the aggressiveness of tumors in breast cancer patients. Int J Oncol 53(5):2289–2299
Pollok KE, Kim SH, Kwon BS (1995) Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4. Eur J Immunol 25(2):488–494
Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33(17):1974–1982
Prokhorov A et al (2015) The immune receptor Tim-3 mediates activation of PI3 kinase/mTOR and HIF-1 pathways in human myeloid leukaemia cells. Int J Biochem Cell Biol 59:11–20
Qian Y et al (2013) B7-H4 enhances oncogenicity and inhibits apoptosis in pancreatic cancer cells. Cell Tissue Res 353(1):139–151
Qin W et al (2015) Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells. Oncotarget 6(37):39839–39854
Rajendran S, Ho WT, Schwarz H (2016) CD137 signaling in Hodgkin and Reed-Sternberg cell lines induces IL-13 secretion, immune deviation and enhanced growth. Oncoimmunology 5(6):e1160188
Rielland M et al (2014) Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression. J Clin Invest 124(5):2125–2135
Riether C et al (2015) Tyrosine kinase inhibitor-induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling. Sci Transl Med 7(298):298ra119
Riether C et al (2017) CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J Exp Med 214(2):359–380
Rivera A et al (2015) Expression of mouse CD47 on human cancer cells profoundly increases tumor metastasis in murine models. BMC Cancer 15:964
Sagawa M et al (2011) A new disulfide-linked dimer of a single-chain antibody fragment against human CD47 induces apoptosis in lymphoid malignant cells via the hypoxia inducible factor-1alpha pathway. Cancer Sci 102(6):1208–1215
Salceda S et al (2005) The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. Exp Cell Res 306(1):128–141
Samaridis J, Colonna M (1997) Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways. Eur J Immunol 27(3):660–665
Seaman S et al (2017) Eradication of tumors through simultaneous ablation of CD276/B7-H3-positive tumor cells and tumor vasculature. Cancer Cell 31(4):501–515 e8
Seaman S et al (2007) Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11(6):539–554
Shan B et al (2016) TIM-3 promotes the metastasis of esophageal squamous cell carcinoma by targeting epithelial-mesenchymal transition via the Akt/GSK-3beta/Snail signaling pathway. Oncol Rep 36(3):1551–1561
Sick E et al (2011) Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway. Glia 59(2):308–319
Sloane DE et al (2004) Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition. Blood 104(9):2832–2839
Suciu-Foca N et al (2007) Soluble Ig-like transcript 3 inhibits tumor allograft rejection in humanized SCID mice and T cell responses in cancer patients. J Immunol 178(11):7432–7441
Sun Y et al (2008) Expression of Ig-like transcript 4 inhibitory receptor in human non-small cell lung cancer. Chest 134(4):783–788
Tamai K et al (2014) Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma. Cancer Sci 105(6):667–674
Tan, W et al (2019) Metformin mediates induction of miR-708 to inhibit self-renewal and chemoresistance of breast cancer stem cells through targeting CD47. J Cell Mol Med
Tedla N et al (2008) Differential expression of leukocyte immunoglobulin-like receptors on cord-blood-derived human mast cell progenitors and mature mast cells. J Leukoc Biol 83(2):334–343
Tekle C et al (2012) B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes. Int J Cancer 130(10):2282–2290
Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461
Tseng D et al (2013) Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A 110(27):11103–11108
Tu X et al (2019) PD-L1 (B7-H1) Competes with the RNA exosome to regulate the DNA damage response and can be targeted to sensitize to radiation or chemotherapy. Mol Cell 74(6):1215–1226 e4
Vinay DS, Kwon BS (2006) Immunotherapy targeting 4-1BB and its ligand. Int J Hematol 83(1):23–28
Vinay DS, Kwon BS (2011) 4-1BB signaling beyond T cells. Cell Mol Immunol 8(4):281–284
Vinay DS, Kwon BS (2012) Immunotherapy of cancer with 4-1BB. Mol Cancer Ther 11(5):1062–1070
Wagtmann N et al (1997) A new human gene complex encoding the killer cell inhibitory receptors and related monocyte/macrophage receptors. Curr Biol 7(8):615–618
Wang Y et al (2015) PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med Oncol 32(8):212
Wang L et al (2016) The tumor suppressor miR-124 inhibits cell proliferation and invasion by targeting B7-H3 in osteosarcoma. Turmour Biol 37(11):14939–14947
Warnecke-Eberz U et al (2016) Diagnostic marker signature for esophageal cancer from transcriptome analysis. Tumour Biol 37(5):6349–6358
Willingham SB et al (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109(17):6662–6667
Wu S et al (2016) Overexpression of B7-H3 correlates with aggressive clinicopathological characteristics in non-small cell lung cancer. Oncotarget 7(49):81750–81756
Xia F et al (2017) B7-H4 enhances the differentiation of murine leukemia-initiating cells via the PTEN/AKT/RCOR2/RUNX1 pathways. Leukemia 31(10):2260–2264
Xiao Z et al (2015) Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett 360(2):302–309
Xie C et al (2016) Soluble B7-H3 promotes the invasion and metastasis of pancreatic carcinoma cells through the TLR4/NF-kappaB pathway. Sci Rep 6:27528
Xu C et al (2014) Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25(5):590–604
Xu JF et al (2015) CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models. Oncotarget 6(27):23662–23670
Yang Y et al (2015) B7-H1 enhances proliferation ability of gastric cancer stem-like cells as a receptor. Oncol Lett 9(4):1833–1838
Yoshida K et al (2015) CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer. Cancer Med 4(9):1322–1333
Zhang Y et al (2012) Expression of immunoglobulin-like transcript (ILT)2 and ILT3 in human gastric cancer and its clinical significance. Mol Med Rep 5(4):910–916
Zhang L et al (2013) The costimulatory molecule B7-H4 promote tumor progression and cell proliferation through translocating into nucleus. Oncogene 32(46):5347–5358
Zhang P et al (2015a) Immunoglobulin-like transcript 4 promotes tumor progression and metastasis and up-regulates VEGF-C expression via ERK signaling pathway in non-small cell lung cancer. Oncotarget 6(15):13550–13563
Zhang H et al (2015b) HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci U S A 112(45):E6215–E6223
Zhang X et al (2017a) Expression and significance of B7-H3 and Tie-2 in the tumor vasculature of clear cell renal carcinoma. Onco Targets Ther 10:5417–5424
Zhang X et al (2017b) B7-H4 promotes tumor growth and metastatic progression in lung cancer by impacting cell proliferation and survival. Oncotarget 8(12):18861–18871
Zhang Y et al (2017c) TIM-3 is a potential prognostic marker for patients with solid tumors: A systematic review and meta-analysis. Oncotarget 8(19):31705–31713
Zhao X et al (2013) B7-H3 overexpression in pancreatic cancer promotes tumor progression. Int J Mol Med 31(2):283–291
Zhao H et al (2016) CD47 Promotes Tumor Invasion and Metastasis in Non-small Cell Lung Cancer. Sci Rep 6:29719
Zheng J et al (2012) Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485(7400):656–660
Zhi Y et al (2015) B7H1 expression and epithelial-to-mesenchymal transition phenotypes on colorectal cancer stem-like cells. PLoS ONE 10(8):e0135528
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Zhang, Y., Zheng, J. (2020). Functions of Immune Checkpoint Molecules Beyond Immune Evasion. In: Xu, J. (eds) Regulation of Cancer Immune Checkpoints. Advances in Experimental Medicine and Biology, vol 1248. Springer, Singapore. https://doi.org/10.1007/978-981-15-3266-5_9
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