Toll-like receptors: New targets for multiple myeloma treatment?

Biochemical Pharmacology - Tập 199 - Trang 114992 - 2022
Olaia Akesolo1, Berta Buey2, Manuel Beltrán-Visiedo1,3, David Giraldos1,3, Isabel Marzo1,3, Eva Latorre1,3
1Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain
2Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
3Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain

Tài liệu tham khảo

LeBlanc, 2021, Management of Myeloma Manifestations and Complications: The Cornerstone of Supportive Care: Recommendation of the Canadian Myeloma Research Group (formerly Myeloma Canada Research Network) Consensus Guideline Consortium, Clin. Lymphoma Myeloma Leuk., S2152–2650, 1 Kristinsson, 2012, Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study, Haematologica, 97, 854, 10.3324/haematol.2011.054015 Krejcik, 2021, Harnessing the Immune System to Fight Multiple Myeloma, Cancers (Basel)., 13, 1, 10.3390/cancers13184546 Lin, 2020, Assessment of infection in newly diagnosed multiple myeloma patients: risk factors and main characteristics, BMC Infect. Dis., 20, 1, 10.1186/s12879-020-05412-w Jego, 2006, Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors, Leukemia, 20, 1130, 10.1038/sj.leu.2404226 Aluri, 2021, Toll-like receptor signaling in the establishment and function of the immune system, Cells, 10, 1, 10.3390/cells10061374 Hiam-Galvez, 2021, Systemic immunity in cancer, Nat. Rev. Cancer, 21, 345, 10.1038/s41568-021-00347-z Shah, 2020, Emerging immunotherapies in multiple myeloma, BMJ., 370, 1 Serrano-del Valle, 2019, Immunogenic cell death and immunotherapy of multiple myeloma, Front. Cell Dev. Biol., 7, 1 Robak, 2018, Drug resistance in multiple myeloma, Cancer Treat. Rev., 70, 199, 10.1016/j.ctrv.2018.09.001 Reynolds, 2013, Toll-like receptor regulation of effector T lymphocyte function, Trends Immunol., 34, 511, 10.1016/j.it.2013.06.003 Hua, 2013, TLR signaling in B-cell development and activation, Cell. Mol. Immunol., 10, 103, 10.1038/cmi.2012.61 Abdi, 2013, Characterization of the Toll-like Receptor Expression Profile in Human Multiple Myeloma Cells, PLoS One, 8, e60671, 10.1371/journal.pone.0060671 Kawasaki, 2014, Toll-Like Receptor Signaling Pathways, Front. Immunol., 5, 1, 10.3389/fimmu.2014.00461 Obermajer, 2018, Promoting the accumulation of tumor-specific T cells in tumor tissues by dendritic cell vaccines and chemokine-modulating agents, Nat. Protoc., 13, 335, 10.1038/nprot.2017.130 Vijay, 2018, Toll-like receptors in immunity and inflammatory diseases: Past, present, and future, Int. Immunopharmacol., 59, 391, 10.1016/j.intimp.2018.03.002 Huang, 2016, Imiquimod activates p53-dependent apoptosis in a human basal cell carcinoma cell line, J. Dermatol. Sci., 81, 182, 10.1016/j.jdermsci.2015.12.011 Hancz, 2018, Flagellin increases death receptor-mediated cell death in a RIP1-dependent manner, Immunol. Lett., 193, 42, 10.1016/j.imlet.2017.11.007 Tye, 2012, STAT3-Driven Upregulation of TLR2 Promotes Gastric Tumorigenesis Independent of Tumor Inflammation, Cancer Cell., 22, 466, 10.1016/j.ccr.2012.08.010 Chochi, 2008, Helicobacter pylori Augments Growth of Gastric Cancers via the Lipopolysaccharide-Toll-like Receptor 4 Pathway whereas Its Lipopolysaccharide Attenuates Antitumor Activities of Human Mononuclear Cells, Clin. Cancer Res., 14, 2909, 10.1158/1078-0432.CCR-07-4467 Kim, 2009, Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis, Nature, 457, 102, 10.1038/nature07623 Ruan, 2014, Activation of Toll-Like Receptor-9 Promotes Cellular Migration via Up-Regulating MMP-2 Expression in Oral Squamous Cell Carcinoma, PLoS One., 9, 10.1371/journal.pone.0092748 Veyrat, 2016, Stimulation of the toll-like receptor 3 promotes metabolic reprogramming in head and neck carcinoma cells, Oncotarget, 7, 82580, 10.18632/oncotarget.12892 Pradere, 2014, The Yin and Yang of Toll-like receptors in cancer, Oncogene, 33, 3485, 10.1038/onc.2013.302 Shi, 2016, Application potential of toll-like receptors in cancer immunotherapy, Medicine (Baltimore), 95, 1, 10.1097/MD.0000000000003951 Xu, 2010, Expression and function of toll-like receptors in multiple myeloma patients: toll-like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor-κB, Br. J. Haematol., 150, 543, 10.1111/j.1365-2141.2010.08284.x Chen, 2017, Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects, Mol. Cancer Res., 15, 598, 10.1158/1541-7786.MCR-16-0293 Takeda, 2003, Toll-Like Receptors, Annu. Rev. Immunol., 21, 335, 10.1146/annurev.immunol.21.120601.141126 Farhat, 2008, Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling, J. Leukoc. Biol., 83, 692, 10.1189/jlb.0807586 Long, 2009, Lipoteichoic Acid Induces Unique Inflammatory Responses when Compared to Other Toll-Like Receptor 2 Ligands, PLoS One, 4, 1, 10.1371/journal.pone.0005601 Patinote, 2020, Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes, Eur. J. Med. Chem., 193, 1, 10.1016/j.ejmech.2020.112238 Wang, 2014, Toll-Like Receptors and Cancer: MYD88 Mutation and Inflammation, Front. Immunol., 5, 1, 10.3389/fimmu.2014.00367 Hirata, 2017, Post-Translational Modifications of the TAK1-TAB Complex, Int. J. Mol. Sci., 18, 1, 10.3390/ijms18010205 Flynn, 2019, Activation of Toll-like Receptor 2 (TLR2) induces Interleukin-6 trans-signaling, Sci. Rep., 9, 7306, 10.1038/s41598-019-43617-5 Chang, 2014, A novel TLR2-triggered signalling crosstalk synergistically intensifies TNF-mediated IL-6 induction, J. Cell. Mol. Med., 18, 1344, 10.1111/jcmm.12294 Kawai, 2010, The role of pattern-recognition receptors in innate immunity: Update on toll-like receptors, Nat. Immunol., 11, 373, 10.1038/ni.1863 Urban-Wojciuk, 2019, The Role of TLRs in Anti-cancer Immunity and Tumor Rejection, Front. Immunol., 10, 1, 10.3389/fimmu.2019.02388 Shimizu, 2018, Immune suppression and reversal of the suppressive tumor microenvironment, Int. Immunol., 30, 445, 10.1093/intimm/dxy042 Liu, 2019, Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2, Int. J. Cancer., 144, 3056, 10.1002/ijc.32060 Scheeren, 2014, A cell-intrinsic role for TLR2–MYD88 in intestinal and breast epithelia and oncogenesis, Nat. Cell Biol., 16, 1238, 10.1038/ncb3058 Muzio, 2009, Expression and function of toll like receptors in chronic lymphocytic leukaemia cells, Br. J. Haematol., 144, 507, 10.1111/j.1365-2141.2008.07475.x Bohnhorst, 2006, Toll-like receptors mediate proliferation and survival of multiple myeloma cells, Leukemia, 20, 1138, 10.1038/sj.leu.2404225 Liu, 2007, Plasma cells from multiple myeloma patients express B7–H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway, Blood, 110, 296, 10.1182/blood-2006-10-051482 Abdi, 2014, Toll-like receptor (TLR)-1/2 triggering of multiple myeloma cells modulates their adhesion to bone marrow stromal cells and enhances bortezomib-induced apoptosis, PLoS One, 9, 1, 10.1371/journal.pone.0096608 Vulpis, 2017, Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis, Oncoimmunology, 6, 1, 10.1080/2162402X.2017.1279372 Belani, 2017, A randomized trial of TLR-2 agonist CADI-05 targeting desmocollin-3 for advanced non-small-cell lung cancer, Ann. Oncol., 28, 298, 10.1093/annonc/mdw608 O’Donnell, 2019, A Clinical Trial of the Intradermal TLR2 Agonist CADI-05 for BCG Recurrent and Unresponsive Non-Muscle Invasive Bladder Cancer, Bl. Cancer, 5, 171, 10.3233/BLC-190211 Dar, 2013, Montanide ISATM 201 adjuvanted FMD vaccine induces improved immune responses and protection in cattle, Vaccine, 31, 3327, 10.1016/j.vaccine.2013.05.078 M. Reilly, R.M. Miller, M.H. Thomson, V. Patris, P. Ryle, L. Mcloughlin, P. Mutch, P. Gilboy, C. Miller, M. Broekema, B. Keogh, W. Mccormack, J. Van De Wetering De Rooij, Randomized, double-blind, placebo-controlled, dose-escalating phase I, healthy subjects study of intravenous OPN-305, a humanized anti-TLR2 antibody, Clin. Pharmacol. Ther. 94 (2013) 593-600. https://doi.org/10.1038/clpt.2013.150. Tarlinton, 2016, RNA expression of TLR10 in normal equine tissues, BMC Res. Notes., 9, 1, 10.1186/s13104-016-2161-9 Hess, 2017, TLR10 suppresses the activation and differentiation of monocytes with effects on DC-mediated adaptive immune responses, J. Leukoc. Biol., 101, 1245, 10.1189/jlb.3A1116-492R Fan, 2019, Toll-like receptor 10 (TLR10) exhibits suppressive effects on inflammation of prostate epithelial cells, Asian J. Androl., 21, 393, 10.4103/aja.aja_100_18 Bourke, 2003, The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells, Blood., 102, 956, 10.1182/blood-2002-11-3355 Chiron, 2009, TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production, J. Immunol., 182, 4471, 10.4049/jimmunol.0803113 Le Naour, 2020, Trial watch: TLR3 agonists in cancer therapy, Oncoimmunology, 9, 1 Harsini, 2014, Toll-like receptors in lymphoid malignancies: Double-edged sword, Crit. Rev. Oncol. Hematol., 89, 262, 10.1016/j.critrevonc.2013.08.010 Braunstein, 2018, Targeting Toll-Like Receptors for Cancer Therapy, Target. Oncol., 13, 583, 10.1007/s11523-018-0589-7 Anwar, 2019, Recent clinical trends in Toll-like receptor targeting therapeutics, Med. Res. Rev., 39, 1053, 10.1002/med.21553 Gjerdingen, 2015 Chen, 2021, Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses, J. Zhejiang Univ. B, 22, 609, 10.1631/jzus.B2000808 Kaczanowska, 2013, TLR agonists: our best frenemy in cancer immunotherapy, J. Leukoc. Biol., 93, 847, 10.1189/jlb.1012501 Chen, 2018, TRIM56 suppresses multiple myeloma progression by activating TLR3/TRIF signaling, Yonsei Med. J., 59, 43, 10.3349/ymj.2018.59.1.43 Abdi, 2011, The role of Toll-like receptor mediated signalling in the pathogenesis of multiple myeloma, Crit. Rev. Oncol. Hematol., 80, 225, 10.1016/j.critrevonc.2010.12.001 Chiron, 2010, Toll-like receptors: Expression and involvement in Multiple Myeloma, Leuk. Res., 34, 1545, 10.1016/j.leukres.2010.06.002 Tartey, 2017, Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells, Int. Rev. Immunol., 36, 57, 10.1080/08830185.2016.1261318 Zhao, 2021, Inflammation and tumor progression: signaling pathways and targeted intervention, Signal Transduct. Target. Ther., 6, 1, 10.1038/s41392-021-00658-5 Thakur, 2015, Role of toll-like receptors in multiple myeloma and recent advances, Exp. Hematol., 43, 158, 10.1016/j.exphem.2014.11.003 Satoh, 2016, Toll-Like Receptor Signaling and Its Inducible Proteins, Microbiol. Spectr., 4, 1, 10.1128/microbiolspec.MCHD-0040-2016 Vacchelli, 2012, Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy, Oncoimmunology, 1, 894, 10.4161/onci.20931 Kumar, 2019, Bacterial Protein Toll-Like-Receptor Agonists: A Novel Perspective on Vaccine Adjuvants, Front. Immunol., 10, 1, 10.3389/fimmu.2019.01144 Basith, 2012, Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense, Arch. Pharm. Res., 35, 1297, 10.1007/s12272-012-0802-7 Monie, 2008, CervarixTM: a vaccine for the prevention of HPV 16, 18-associated cervical cancer, Biol. Targets Ther., 2, 107 Chiang, 2011, Adjuvants for Enhancing the Immunogenicity of Whole Tumor Cell Vaccines, Int. Rev. Immunol., 30, 150, 10.3109/08830185.2011.572210 Bhatia, 2019, Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma, Clin. Cancer Res., 25, 1185, 10.1158/1078-0432.CCR-18-0469 Ong, 2021, Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants, Front. Cell. Infect. Microbiol., 11, 1, 10.3389/fcimb.2021.745016 Bao, 2011, Triggering of toll-like receptor-4 in human multiple myeloma cells promotes proliferation and alters cell responses to immune and chemotherapy drug attack, Cancer Biol. Ther., 11, 58, 10.4161/cbt.11.1.13878 Nakamura, 2018, Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment, Cancer Cell., 33, 634, 10.1016/j.ccell.2018.02.007 Bagratuni, 2019, Toll-Like Receptor 4 Activation Promotes Multiple Myeloma Cell Growth and Survival Via Suppression of The Endoplasmic Reticulum Stress Factor Chop, Sci. Rep., 9, 10.1038/s41598-019-39672-7 C. Giallongo, D. Tibullo, F. Puglisi, A. Barbato, N. Vicario, D. Cambria, N.L. Parrinello, A. Romano, C. Conticello, S. Forte, R. Parenti, A.M. Amorini, G. Lazzarino, G. Li Volti, G.A. Palumbo, F. Di Raimondo, Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells, Cancers (Basel). 12 (2020) 1999. https://doi.org/10.3390/cancers12081999. Gao, 2016, Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway, Mol. Med. Rep., 13, 1827, 10.3892/mmr.2015.4703 L. Lemaitre, M. Hamaidia, J.-G. Descamps, L. Do Souto Ferreira, M.V. Joubert, M. Gadelorge, H. Avet-Loiseau, A. Justo, N. Reina, F. Deschaseaux, L. Martinet, P. Bourin, J. Corre, N. Espagnolle, Toll-like receptor 4 selective inhibition in medullar microenvironment alters multiple myeloma cell growth, Blood Adv. (2021). https://doi.org/10.1182/bloodadvances.2020003704. Cho, 2014, TLR5 activation by flagellin induces doxorubicin resistance via interleukin-6 (IL-6) expression in two multiple myeloma cells, Cell. Immunol., 289, 27, 10.1016/j.cellimm.2014.03.003 Isaza-Correa, 2014, Toll-like receptors in the pathogenesis of human B cell malignancies, J. Hematol. Oncol., 7, 1, 10.1186/s13045-014-0057-5 Hajam, 2017, Bacterial flagellin-a potent immunomodulatory agent, Exp. Mol. Med., 49, 1, 10.1038/emm.2017.172 Cui, 2018, Flagellin as a vaccine adjuvant, Expert Rev. Vaccines, 17, 335, 10.1080/14760584.2018.1457443 Brackett, 2016, Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis, Proc. Natl. Acad. Sci., 113, E874, 10.1073/pnas.1521359113 Dajon, 2016, Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword, Immunobiology, 222, 89, 10.1016/j.imbio.2016.06.009 Luchner, 2021, TLR Agonists as Vaccine Adjuvants Targeting Cancer and Infectious Diseases, Pharmaceutics, 13, 1, 10.3390/pharmaceutics13020142 Bender, 2020, TLR7 and TLR8 Differentially Activate the IRF and NF-κB Pathways in Specific Cell Types to Promote Inflammation, ImmunoHorizons, 4, 93, 10.4049/immunohorizons.2000002 Zhang, 2018, TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG, J. Exp. Med., 215, 3019, 10.1084/jem.20180800 Vierbuchen, 2019, RNA is taking its Toll: Impact of RNA-specific Toll-like receptors on health and disease, Allergy, 74, 223, 10.1111/all.13680 Huang, 2021, Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics, Expert Opin. Drug Discov., 16, 869, 10.1080/17460441.2021.1898369 Grimmig, 2015, TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer, Int. J. Oncol., 47, 857, 10.3892/ijo.2015.3069 Liu, 2015, Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity, Cancer Cell Int., 15, 1, 10.1186/s12935-015-0260-7 Michaelis, 2019, The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer, Nat. Commun., 10, 1 Yin, 2015, Toll-like receptor 7/8 agonist, R848, exhibits antitumoral effects in a breast cancer model, Mol. Med. Rep., 12, 3515, 10.3892/mmr.2015.3885 Grimm, 2010, Toll-like receptor (TLR) 7 and TLR8 expression on CD133+ cells in colorectal cancer points to a specific role for inflammation-induced TLRs in tumourigenesis and tumour progression, Eur. J. Cancer, 46, 2849, 10.1016/j.ejca.2010.07.017 Gu, 2017, Roles of toll-like receptors: From inflammation to lung cancer progression (Review), Biomed. Rep., 8, 126 Sheyhidin, 2011, Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma, World J. Gastroenterol., 17, 3745, 10.3748/wjg.v17.i32.3745 Zhang, 2017, Toll-like receptors 7 and 8 expression correlates with the expression of immune biomarkers and positively predicts the clinical outcome of patients with melanoma, Onco. Targets. Ther., 10, 4339, 10.2147/OTT.S136194 Smits, 2008, The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy, Oncologist, 13, 859, 10.1634/theoncologist.2008-0097 Bauer, 2001, Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition, Proc. Natl. Acad. Sci., 98, 9237, 10.1073/pnas.161293498 Ohto, 2015, Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9, Nature, 520, 702, 10.1038/nature14138 Reikine, 2020, Equilibrium Binding Model for CpG DNA-Dependent Dimerization of Toll-like Receptor 9 Ectodomain, Biochemistry, 59, 4155, 10.1021/acs.biochem.0c00466 Lee, 2014, Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product, J. Immunol., 193, 3726, 10.4049/jimmunol.1400210 Lamphier, 2006, TLR9 and the Recognition of Self and Non-Self Nucleic Acids, Ann. NY Acad. Sci., 1082, 31, 10.1196/annals.1348.005 McCarthy, 2016, Immunostimulatory role of mitochondrial DAMPs: alarming for pre-eclampsia?, Am. J. Reprod. Immunol., 76, 341, 10.1111/aji.12526 Leadbetter, 2002, Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors, Nature, 416, 603, 10.1038/416603a Tian, 2007, Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE, Nat. Immunol., 8, 487, 10.1038/ni1457 Agrawal, 2011, TLR1/2, TLR7, and TLR9 Signals Directly Activate Human Peripheral Blood Naive and Memory B Cell Subsets to Produce Cytokines, Chemokines, and Hematopoietic Growth Factors, J. Clin. Immunol., 31, 89, 10.1007/s10875-010-9456-8 Carbone, 2021, Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer, J. Immunother. Cancer, 9, 1, 10.1136/jitc-2021-002876 Xu, 2019, TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis, Cell. Mol. Immunol., 16, 820, 10.1038/s41423-018-0184-y Zhang, 2012, An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy, PLoS One, 7, 1 Humbert, 2018, Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC, Cancer Res., 78, 3280, 10.1158/0008-5472.CAN-17-2549 Wang, 2016, Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8 + T cells, Proc. Natl. Acad. Sci., 113, e7240, 10.1073/pnas.1608555113 Adamus, 2018, The revival of CpG oligonucleotide-based cancer immunotherapies, Contemp Oncol., 22, 56 Le Noci, 2015, Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment, Oncoimmunology, 4, 1, 10.1080/2162402X.2015.1040214 Shen, 2020, Liposomal TLR9 Agonist Combined with TLR2 Agonist-Fused Antigen Can Modulate Tumor Microenvironment through Dendritic Cells, Cancers (Basel)., 12, 1, 10.3390/cancers12040810 Bi, 2018, E-cadherin expression on multiple myeloma cells activates tumor-promoting properties in plasmacytoid DCs, J. Clin. Invest., 128, 4821, 10.1172/JCI121421 Ray, 2014, A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib, Leukemia, 28, 1716, 10.1038/leu.2014.46 Song, 2015, A TLR9 agonist enhances the anti-tumor immunity of peptide and lipopeptide vaccines via different mechanisms, Sci. Rep., 5, 1 Wijdenes, 1996, A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1, Br. J. Haematol., 94, 318, 10.1046/j.1365-2141.1996.d01-1811.x Smith, 2006, Helicobacter pylori and toll-like receptor agonists induce syndecan-4 expression in an NF-κB-dependent manner, Glycobiology, 16, 221, 10.1093/glycob/cwj061 Kouwenberg, 2020, Role of syndecan-1 in the interaction between dendritic cells and T cells, PLoS One, 15, 1, 10.1371/journal.pone.0230835 Bhagwani, 2020, When Innate Immunity Meets Angiogenesis—The Role of Toll-Like Receptors in Endothelial Cells and Pulmonary Hypertension, Front. Med., 7, 1, 10.3389/fmed.2020.00352 Jeong, 2021, Engineering Therapeutic Strategies in Cancer Immunotherapy via Exogenous Delivery of Toll-like Receptor Agonists, Pharmaceutics, 13, 1, 10.3390/pharmaceutics13091374 Howell, 2021, Bacteria-based immune therapies for cancer treatment, Semin. Cancer Biol., 1 Termeer, 2002, Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4, J. Exp. Med., 195, 99, 10.1084/jem.20001858 Schaefer, 2014, Complexity of danger: the diverse nature of damage-associated molecular patterns, J. Biol. Chem., 289, 35237, 10.1074/jbc.R114.619304 Biragyn, 2008, Murine -defensin 2 promotes TLR-4/MyD88-mediated and NF- B-dependent atypical death of APCs via activation of TNFR2, J. Leukoc. Biol., 83, 998, 10.1189/jlb.1007700 Amarante-Mendes, 2018, Pattern recognition receptors and the host cell death molecular machinery, Front. Immunol., 9, 1, 10.3389/fimmu.2018.02379 Schaefer, 2005, The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages, J. Clin. Invest., 115, 2223, 10.1172/JCI23755 Matsumura, 2016, Peroxiredoxin 1 Contributes to Host Defenses against Mycobacterium tuberculosis, J. Immunol., 197, 3233, 10.4049/jimmunol.1601010 Yu, 2010, Endogenous toll-like receptor ligands and their biological significance, J. Cell. Mol. Med., 14, 2592, 10.1111/j.1582-4934.2010.01127.x Chiron, 2008, Toll-like receptors: lessons to learn from normal and malignant human B cells, Blood, 112, 2205, 10.1182/blood-2008-02-140673 Okamura, 2001, The Extra Domain A of Fibronectin Activates Toll-like Receptor 4, J. Biol. Chem., 276, 10229, 10.1074/jbc.M100099200 Johnson, 2002, Receptor-Mediated Monitoring of Tissue Well-Being Via Detection of Soluble Heparan Sulfate by Toll-Like Receptor 4, J. Immunol., 168, 5233, 10.4049/jimmunol.168.10.5233 Smiley, 2001, Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4, J. Immunol., 167, 2887, 10.4049/jimmunol.167.5.2887 Guillot, 2002, Cutting edge: the immunostimulatory activity of the lung surfactant protein-a involves toll-like receptor 4, J. Immunol., 168, 5989, 10.4049/jimmunol.168.12.5989 Midwood, 2009, Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease, Nat. Med., 15, 774, 10.1038/nm.1987 McCarthy, 2014, Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension, Am. J. Physiol. Circ. Physiol., 306, 184, 10.1152/ajpheart.00328.2013