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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Perspectives on immune checkpoint ligands: expression, regulation, and clinical implications

  • Moon, Jihyun (Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University) ;
  • Oh, Yoo Min (Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University) ;
  • Ha, Sang-Jun (Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University)
  • Received : 2021.03.23
  • Accepted : 2021.05.14
  • Published : 2021.08.31
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Abstract

In the tumor microenvironment, immune checkpoint ligands (ICLs) must be expressed in order to trigger the inhibitory signal via immune checkpoint receptors (ICRs). Although ICL expression frequently occurs in a manner intrinsic to tumor cells, extrinsic factors derived from the tumor microenvironment can fine-tune ICL expression by tumor cells or prompt non-tumor cells, including immune cells. Considering the extensive interaction between T cells and other immune cells within the tumor microenvironment, ICL expression on immune cells can be as significant as that of ICLs on tumor cells in promoting antitumor immune responses. Here, we introduce various regulators known to induce or suppress ICL expression in either tumor cells or immune cells, and concise mechanisms relevant to their induction. Finally, we focus on the clinical significance of understanding the mechanisms of ICLs for an optimized immunotherapy for individual cancer patients.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2017R1A5A1014560, 2019M3A9B6065221) and by the National Institute of Biological Resources funded by the Ministry of Environment (MOE) (NIBR202122202). This study was also supported by the Korean Health Technology R&D Project (HV20C0144) through the Korean Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  1. Patsoukis N, Wang Q, Strauss L and Boussiotis VA (2020) Revisiting the PD-1 pathway. Sci Adv 6, eabd2712 https://doi.org/10.1126/sciadv.abd2712
  2. Marin-Acevedo JA, Kimbrough EO and Lou Y (2021) Next generation of immune checkpoint inhibitors and beyond. J Hematol Oncol 14, 45 https://doi.org/10.1186/s13045-021-01056-8
  3. Anderson AC, Joller N and Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989-1004 https://doi.org/10.1016/j.immuni.2016.05.001
  4. Chihara N, Madi A, Kondo T et al (2018) Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558, 454-459 https://doi.org/10.1038/s41586-018-0206-z
  5. Yadollahi P, Jeon YK, Ng WL and Choi I (2021) Current understanding of cancer-intrinsic PD-L1: regulation of expression and its protumoral activity. BMB Rep 54, 12-20 https://doi.org/10.5483/BMBRep.2021.54.1.241
  6. Yu Y, Liang Y, Li D et al (2021) Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment. Cell Death Discov 7, 15
  7. Byun JK, Park M, Lee S et al (2020) Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Mol Cell 80, 592-606 e598 https://doi.org/10.1016/j.molcel.2020.10.015
  8. Feng J, Yang H, Zhang Y et al (2017) Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 36, 5829-5839 https://doi.org/10.1038/onc.2017.188
  9. Barsoum IB, Smallwood CA, Siemens DR and Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74, 665-674 https://doi.org/10.1158/0008-5472.CAN-13-0992
  10. Dong H, Strome SE, Salomao DR et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8, 793-800 https://doi.org/10.1038/nm730
  11. Garcia-Diaz A, Shin DS, Moreno BH et al (2017) interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep 19, 1189-1201 https://doi.org/10.1016/j.celrep.2017.04.031
  12. Lim SO, Li CW, Xia W et al (2016) Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell 30, 925-939 https://doi.org/10.1016/j.ccell.2016.10.010
  13. Wang X, Yang L, Huang F et al (2017) Inflammatory cytokines IL-17 and TNF-alpha up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol Lett 184, 7-14 https://doi.org/10.1016/j.imlet.2017.02.006
  14. Quandt D, Jasinski-Bergner S, Muller U, Schulze B and Seliger B (2014) Synergistic effects of IL-4 and TNFalpha on the induction of B7-H1 in renal cell carcinoma cells inhibiting allogeneic T cell proliferation. J Transl Med 12, 151 https://doi.org/10.1186/1479-5876-12-151
  15. Xu L, Chen X, Shen M et al (2018) Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Mol Oncol 12, 269-286 https://doi.org/10.1002/1878-0261.12135
  16. Shen MJ, Xu LJ, Yang L et al (2017) Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway. Oncotarget 8, 80506-80520 https://doi.org/10.18632/oncotarget.19193
  17. Chan LC, Li CW, Xia W et al (2019) IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest 129, 3324-3338 https://doi.org/10.1172/JCI126022
  18. Carbotti G, Barisione G, Airoldi I et al (2015) IL-27 induces the expression of IDO and PD-L1 in human cancer cells. Oncotarget 6, 43267-43280 https://doi.org/10.18632/oncotarget.6530
  19. David JM, Dominguez C, McCampbell KK, Gulley JL, Schlom J and Palena C (2017) A novel bifunctional anti-PD-L1/TGF-beta Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology 6, e1349589 https://doi.org/10.1080/2162402X.2017.1349589
  20. Qian Y, Deng J, Geng L et al (2008) TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells. Cancer Invest 26, 816-821 https://doi.org/10.1080/07357900801941852
  21. Boes M and Meyer-Wentrup F (2015) TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells. Cancer Lett 361, 49-56 https://doi.org/10.1016/j.canlet.2015.02.027
  22. Yamashita K, Iwatsuki M, Harada K et al (2020) Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. Gastric Cancer 23, 95-104 https://doi.org/10.1007/s10120-019-00999-9
  23. Shklovskaya E and Rizos H (2020) Spatial and temporal changes in pd-l1 expression in cancer: the role of genetic drivers, tumor microenvironment and resistance to therapy. Int J Mol Sci 21, 7139 https://doi.org/10.3390/ijms21197139
  24. Brown JA, Dorfman DM, Ma FR et al (2003) Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 170, 1257-1266 https://doi.org/10.4049/jimmunol.170.3.1257
  25. Muthumani K, Shedlock DJ, Choo DK et al (2011) HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells. J Immunol 187, 2932-2943 https://doi.org/10.4049/jimmunol.1100594
  26. Kryczek I, Wei S, Gong W et al (2008) Cutting edge: IFN-gamma enables APC to promote memory Th17 and abate Th1 cell development. J Immunol 181, 5842-5846 https://doi.org/10.4049/jimmunol.181.9.5842
  27. de Kleijn S, Langereis JD, Leentjens J et al (2013) IFN-gamma-stimulated neutrophils suppress lymphocyte proliferation through expression of PD-L1. PLoS One 8, e72249 https://doi.org/10.1371/journal.pone.0072249
  28. Schreiner B, Mitsdoerffer M, Kieseier BC et al (2004) Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 155, 172-182 https://doi.org/10.1016/j.jneuroim.2004.06.013
  29. Karakhanova S, Meisel S, Ring S, Mahnke K and Enk AH (2010) ERK/p38 MAP-kinases and PI3K are involved in the differential regulation of B7-H1 expression in DC subsets. Eur J Immunol 40, 254-266 https://doi.org/10.1002/eji.200939289
  30. Ou JN, Wiedeman AE and Stevens AM (2012) TNF-alpha and TGF-beta counter-regulate PD-L1 expression on monocytes in systemic lupus erythematosus. Sci Rep 2, 295 https://doi.org/10.1038/srep00295
  31. Hartley G, Regan D, Guth A and Dow S (2017) Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNFalpha. Cancer Immunol Immunother 66, 523-535 https://doi.org/10.1007/s00262-017-1955-5
  32. Zhang W, Liu Y, Yan Z et al (2020) IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. J Immunother Cancer 8
  33. Zhao Q, Xiao X, Wu Y et al (2011) Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Eur J Immunol 41, 2314-2322 https://doi.org/10.1002/eji.201041282
  34. Xiong HY, Ma TT, Wu BT, Lin Y and Tu ZG (2014) IL-12 regulates B7-H1 expression in ovarian cancer-associated macrophages by effects on NF-kappaB signalling. Asian Pac J Cancer Prev 15, 5767-5772 https://doi.org/10.7314/APJCP.2014.15.14.5767
  35. Jiang C, Yuan F, Wang J and Wu L (2017) Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages. Immunobiology 222, 651-657 https://doi.org/10.1016/j.imbio.2016.12.002
  36. Taube JM, Young GD, McMiller TL et al (2015) Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 21, 3969-3976 https://doi.org/10.1158/1078-0432.CCR-15-0244
  37. Curiel TJ, Wei S, Dong H et al (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9, 562-567 https://doi.org/10.1038/nm863
  38. Song S, Yuan P, Wu H et al (2014) Dendritic cells with an increased PD-L1 by TGF-beta induce T cell anergy for the cytotoxicity of hepatocellular carcinoma cells. Int Immunopharmacol 20, 117-123 https://doi.org/10.1016/j.intimp.2014.02.027
  39. Ni XY, Sui HX, Liu Y, Ke SZ, Wang YN and Gao FG (2012) TGF-beta of lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generation. Oncol Rep 28, 615-621 https://doi.org/10.3892/or.2012.1822
  40. Pulko V, Liu X, Krco CJ et al (2009) TLR3-stimulated dendritic cells up-regulate B7-H1 expression and influence the magnitude of CD8 T cell responses to tumor vaccination. J Immunol 183, 3634-3641 https://doi.org/10.4049/jimmunol.0900974
  41. Huang G, Wen Q, Zhao Y, Gao Q and Bai Y (2013) NF-kappaB plays a key role in inducing CD274 expression in human monocytes after lipopolysaccharide treatment. PLoS One 8, e61602 https://doi.org/10.1371/journal.pone.0061602
  42. Loke P and Allison JP (2003) PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A 100, 5336-5341 https://doi.org/10.1073/pnas.0931259100
  43. Mezzadra R, Sun C, Jae LT et al (2017) Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature 549, 106-110 https://doi.org/10.1038/nature23669
  44. Prima V, Kaliberova LN, Kaliberov S, Curiel DT and Kusmartsev S (2017) COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci U S A 114, 1117-1122 https://doi.org/10.1073/pnas.1612920114
  45. Youngnak P, Kozono Y, Kozono H et al (2003) Differential binding properties of B7-H1 and B7-DC to programmed death-1. Biochem Biophys Res Commun 307, 672-677 https://doi.org/10.1016/S0006-291X(03)01257-9
  46. Zhong X, Tumang JR, Gao W, Bai C and Rothstein TL (2007) PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 37, 2405-2410 https://doi.org/10.1002/eji.200737461
  47. Wang H, Yao H, Li C et al (2017) PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation. Oncoimmunology 6, e1327494 https://doi.org/10.1080/2162402X.2017.1327494
  48. Fu Y, Liu CJ, Kobayashi DK et al (2020) GATA2 regulates constitutive PD-L1 and PD-L2 expression in brain tumors. Sci Rep 10, 9027 https://doi.org/10.1038/s41598-020-65915-z
  49. Derks S, Nason KS, Liao X et al (2015) Epithelial PD-L2 expression marks Barrett's esophagus and esophageal adenocarcinoma. Cancer Immunol Res 3, 1123-1129 https://doi.org/10.1158/2326-6066.CIR-15-0046
  50. Latchman Y, Wood CR, Chernova T et al (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2, 261-268 https://doi.org/10.1038/85330
  51. Yamazaki T, Akiba H, Iwai H et al (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169, 5538-5545 https://doi.org/10.4049/jimmunol.169.10.5538
  52. Huber S, Hoffmann R, Muskens F and Voehringer D (2010) Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2. Blood 116, 3311-3320
  53. Inaba K, Yashiro T, Hiroki I, Watanabe R, Kasakura K and Nishiyama C (2020) Dual roles of PU.1 in the expression of PD-L2: direct transactivation with IRF4 and indirect epigenetic regulation. J Immunol 205, 822-829 https://doi.org/10.4049/jimmunol.1901008
  54. Kinter AL, Godbout EJ, McNally JP et al (2008) The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 181, 6738-6746 https://doi.org/10.4049/jimmunol.181.10.6738
  55. Yu X, Harden K, Gonzalez LC et al (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10, 48-57 https://doi.org/10.1038/ni.1674
  56. Masson D, Jarry A, Baury B et al (2001) Overexpression of the CD155 gene in human colorectal carcinoma. Gut 49, 236-240 https://doi.org/10.1136/gut.49.2.236
  57. Nakai R, Maniwa Y, Tanaka Y et al (2010) Overexpression of Necl-5 correlates with unfavorable prognosis in patients with lung adenocarcinoma. Cancer Sci 101, 1326-1330 https://doi.org/10.1111/j.1349-7006.2010.01530.x
  58. Bevelacqua V, Bevelacqua Y, Candido S et al (2012) Nectin like-5 overexpression correlates with the malignant phenotype in cutaneous melanoma. Oncotarget 3, 882-892 https://doi.org/10.18632/oncotarget.594
  59. Triki H, Charfi S, Bouzidi L et al (2019) CD155 expression in human breast cancer: clinical significance and relevance to natural killer cell infiltration. Life Sci 231, 116543 https://doi.org/10.1016/j.lfs.2019.116543
  60. Hirota T, Irie K, Okamoto R, Ikeda W and Takai Y (2005) Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway. Oncogene 24, 2229-2235 https://doi.org/10.1038/sj.onc.1208409
  61. Schummer P, Kuphal S, Vardimon L, Bosserhoff AK and Kappelmann M (2016) Specific c-Jun target genes in malignant melanoma. Cancer Biol Ther 17, 486-497 https://doi.org/10.1080/15384047.2016.1156264
  62. Martinet L and Smyth MJ (2015) Balancing natural killer cell activation through paired receptors. Nat Rev Immunol 15, 243-254 https://doi.org/10.1038/nri3799
  63. Fionda C, Abruzzese MP, Zingoni A et al (2015) Nitric oxide donors increase PVR/CD155 DNAM-1 ligand expression in multiple myeloma cells: role of DNA damage response activation. BMC Cancer 15, 17 https://doi.org/10.1186/s12885-015-1023-5
  64. Soriani A, Zingoni A, Cerboni C et al (2009) ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113, 3503-3511 https://doi.org/10.1182/blood-2008-08-173914
  65. Fionda C, Abruzzese MP, Zingoni A et al (2015) The IMiDs targets IKZF-1/3 and IRF4 as novel negative regulators of NK cell-activating ligands expression in multiple myeloma. Oncotarget 6, 23609-23630 https://doi.org/10.18632/oncotarget.4603
  66. Gong J, Fang L, Liu R et al (2014) UPR decreases CD226 ligand CD155 expression and sensitivity to NK cell-mediated cytotoxicity in hepatoma cells. Eur J Immunol 44, 3758-3767 https://doi.org/10.1002/eji.201444574
  67. Zitti B, Molfetta R, Fionda C et al (2017) Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells. Sci Rep 7, 10445 https://doi.org/10.1038/s41598-017-10403-0
  68. Stanietsky N, Rovis TL, Glasner A et al (2013) Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur J Immunol 43, 2138-2150 https://doi.org/10.1002/eji.201243072
  69. Chauvin JM, Pagliano O, Fourcade J et al (2015) TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest 125, 2046-2058 https://doi.org/10.1172/JCI80445
  70. Kamran N, Takai Y, Miyoshi J, Biswas SK, Wong JS and Gasser S (2013) Toll-like receptor ligands induce expression of the costimulatory molecule CD155 on antigen-presenting cells. PLoS One 8, e54406 https://doi.org/10.1371/journal.pone.0054406
  71. Rangachari M, Zhu C, Sakuishi K et al (2012) Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med 18, 1394-1400 https://doi.org/10.1038/nm.2871
  72. Huang YH, Zhu C, Kondo Y et al (2015) CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517, 386-390 https://doi.org/10.1038/nature13848
  73. Yang R, Sun L, Li CF et al (2021) Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun 12, 832 https://doi.org/10.1038/s41467-021-21099-2
  74. Li H, Wu K, Tao K et al (2012) Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56, 1342-1351 https://doi.org/10.1002/hep.25777
  75. Wiener Z, Kohalmi B, Pocza P et al (2007) TIM-3 is expressed in melanoma cells and is upregulated in TGF-beta stimulated mast cells. J Invest Dermatol 127, 906-914 https://doi.org/10.1038/sj.jid.5700616
  76. Kammerer R, Stober D, Singer BB, Obrink B and Reimann J (2001) Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J Immunol 166, 6537-6544 https://doi.org/10.4049/jimmunol.166.11.6537
  77. Horst AK, Bickert T, Brewig N et al (2009) CEACAM1+ myeloid cells control angiogenesis in inflammation. Blood 113, 6726-6736 https://doi.org/10.1182/blood-2008-10-184556
  78. Gebauer F, Wicklein D, Horst J et al (2014) Carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1, 5 and 6 as biomarkers in pancreatic cancer. PLoS One 9, e113023 https://doi.org/10.1371/journal.pone.0113023
  79. Dardalhon V, Anderson AC, Karman J et al (2010) Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J Immunol 185, 1383-1392 https://doi.org/10.4049/jimmunol.0903275
  80. Zhou J, Jiang Y, Zhang H et al (2019) Clinicopathological implications of TIM3(+) tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients. Cancer Immunol Immunother 68, 1157-1169 https://doi.org/10.1007/s00262-019-02349-1
  81. Yang Q, Jiang W, Zhuang C et al (2015) microRNA-22 downregulation of galectin-9 influences lymphocyte apoptosis and tumor cell proliferation in liver cancer. Oncol Rep 34, 1771-1778 https://doi.org/10.3892/or.2015.4167
  82. Zhang L, Tian S, Zhao M et al (2020) SUV39H1-DNMT3Amediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer. Cancer Cell Int 20, 325 https://doi.org/10.1186/s12935-020-01380-y
  83. Maruhashi T, Okazaki IM, Sugiura D et al (2018) LAG-3 inhibits the activation of CD4(+) T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol 19, 1415-1426 https://doi.org/10.1038/s41590-018-0217-9
  84. Reith W, LeibundGut-Landmann S and Waldburger JM (2005) Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol 5, 793-806 https://doi.org/10.1038/nri1708
  85. Kouo T, Huang L, Pucsek AB et al (2015) Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res 3, 412-423 https://doi.org/10.1158/2326-6066.CIR-14-0150
  86. Xu F, Liu J, Liu D et al (2014) LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res 74, 3418-3428 https://doi.org/10.1158/0008-5472.CAN-13-2690
  87. Wang J, Sanmamed MF, Datar I et al (2019) Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell 176, 334-347 e312 https://doi.org/10.1016/j.cell.2018.11.010
  88. Nakahara S, Oka N and Raz A (2005) On the role of galectin-3 in cancer apoptosis. Apoptosis 10, 267-275 https://doi.org/10.1007/s10495-005-0801-y
  89. Fei F, Joo EJ, Tarighat SS et al (2015) B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3. Oncotarget 6, 11378-11394 https://doi.org/10.18632/oncotarget.3409
  90. Kim K, Mayer EP and Nachtigal M (2003) Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins. Biochim Biophys Acta 1641, 13-23 https://doi.org/10.1016/S0167-4889(03)00045-4
  91. Liu L, Sakai T, Sano N and Fukui K (2004) Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling. Biochem J 380, 31-41 https://doi.org/10.1042/bj20031300
  92. Dominguez-Soto A, Aragoneses-Fenoll L, Martin-Gayo E et al (2007) The DC-SIGN-related lectin LSECtin mediates antigen capture and pathogen binding by human myeloid cells. Blood 109, 5337-5345 https://doi.org/10.1182/blood-2006-09-048058
  93. Liu Z and Ukomadu C (2008) Fibrinogen-like protein 1, a hepatocyte derived protein is an acute phase reactant. Biochem Biophys Res Commun 365, 729-734 https://doi.org/10.1016/j.bbrc.2007.11.069
  94. Doroshow DB, Bhalla S, Beasley MB et al (2021) PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol 18, 345-362 https://doi.org/10.1038/s41571-021-00473-5
  95. Lee BR, Chae S, Moon J et al (2020) Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade. JCI Insight 5, e128633 https://doi.org/10.1172/jci.insight.128633
  96. Yonesaka K, Haratani K, Takamura S et al (2018) B7-H3 negatively modulates ctl-mediated cancer immunity. Clin Cancer Res 24, 2653-2664 https://doi.org/10.1158/1078-0432.CCR-17-2852