针对IL-4/IL-4R信号通路的肿瘤治疗策略研究进展
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摘要
目前对于原发性上皮肿瘤的治疗已取得较多进展,但转移性肿瘤死亡率仍很高,且针对转移性肿瘤治疗的进展有限。研究表明,IL-4/IL-4R信号通路不仅在免疫系统中具有很重要的作用,且IL-4R在很多上皮肿瘤细胞中有过表达的现象,IL-4/IL-4R信号通路在上皮肿瘤的存活、增殖、迁移和侵袭中具有很强的促进作用。美国FDA已批准了几种靶向IL-4/IL-4R信号通路的药物用于哮喘的治疗,目前这些药物均又被用于肿瘤治疗的开发。综述针对IL-4/IL-4R信号通路的肿瘤治疗策略研究进展,分析近年来一些新的靶向IL-4/IL-4R的肿瘤治疗方法,旨在为相关药物的研发提供参考。
Currently, significant progress has been made in the treatment of primary epithelial tumors. However, the mortality rate of metastatic tumor remains very high and limited progress has been made in its treatment. Studies have shown that IL-4/IL-4R signaling pathway not only plays an essential role in the immune system but also has a strong promoting effect on the survival, proliferation, migration, and invasion of epithelial tumor cells due to its overexpression in several types of epithelial tumor cells. FDA has approved several drugs targeting IL-4/IL-4R signaling pathway for the treatment of asthma. These drugs are currently under the development for cancer treatment. This article reviewed research advances in tumor therapeutic strategies that target IL-4/IL-4R signaling pathway and analyzed some recently developed new therapeutic strategies targeting IL-4/IL-4R pathway, so as to provide reference for the research and development of new drugs.
Currently, significant progress has been made in the treatment of primary epithelial tumors. However, the mortality rate of metastatic tumor remains very high and limited progress has been made in its treatment. Studies have shown that IL-4/IL-4R signaling pathway not only plays an essential role in the immune system but also has a strong promoting effect on the survival, proliferation, migration, and invasion of epithelial tumor cells due to its overexpression in several types of epithelial tumor cells. FDA has approved several drugs targeting IL-4/IL-4R signaling pathway for the treatment of asthma. These drugs are currently under the development for cancer treatment. This article reviewed research advances in tumor therapeutic strategies that target IL-4/IL-4R signaling pathway and analyzed some recently developed new therapeutic strategies targeting IL-4/IL-4R pathway, so as to provide reference for the research and development of new drugs.
引文
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[23]Guo C,Ouyang Y,Cai J,et al.High expression of IL-4R enhances proliferation and invasion of hepatocellular carcinoma cells[J].Int JBiol Markers,2017,32(4):e384-e390.
[24]Li G,Kikuchi K,Radka M,et al.IL-4 receptor blockade abrogates satellite cell:rhabdomyosarcoma fusion and prevents tumor establishment[J].Stem Cells,2013,31(11):2304-2312.
[25]Barik S,Cattin-Roy A N,Miller M M,et al.IL-4 and IL-13 guide early thymic progenitors to mature toward dendritic cells[J].J Immunol,2018,201(10):2947-2958.
[26]Oh C K,Geba G P,Molfino N.Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma[J].Eur Respir Rev,2010,19(115):46-54.
[27]Delgoffe G M,Kole T P,Zheng Y,et al.The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment[J].Immunity,2009,30(6):832-844.
[28]Gandhi N A,Bennett B L,Graham N M,et al.Targeting key proximal drivers of type 2 inflammation in disease[J].Nat Rev Drug Discov,2016,15(1):35-50.
[29]Bagnasco D,Ferrando M,Varricchi G,et al.A critical evaluation of anti-IL-13 and anti-IL-4 strategies in severe asthma[J].Int Arch Allergy Immunol,2016,170(2):122-131.
[30]Hamilton M J,Bosiljcic M,Lepard N E,et al.Macrophages are more potent immune suppressors ex vivo than immature myeloid-derived suppressor cells induced by metastatic murine mammary carcinomas[J].J Immunol,2014,192(1):512-522.
[31]Marvel D,Gabrilovich D I.Myeloid-derived suppressor cells in the tumor microenvironment:expect the unexpected[J].J Clin Invest,2015,125(9):3356-3364.
[32]Tanaka T.Flavonoids for allergic diseases:present evidence and future perspective[J].Curr Pharm Des,2014,20(6):879-885.
[33]Cai J,Zhao X L,Liu A W,et al.Apigenin inhibits hepatoma cell growth through alteration of gene expression patterns[J].Phytomedicine,2011,18(5):366-373.
[34]Xu X,Zheng Y,Zhang X,et al.Efficacy and safety of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults[J].Oncotarget,2017,8(65):108480-108491.
[35]Agrawal S,Townley R G.Role of periostin,FENO,IL-13,lebrikzumab,other IL-13 antagonist and dual IL-4/IL-13 antagonist in asthma[J].Expert Opin Biol Ther,2014,14(2):165-181.
[36]Tomkinson A,Tepper J,Morton M,et al.Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma[J].Allergy,2010,65(1):69-77.
[37]Kreitman R J,Puri R K,Leland P,et al.Site-specific conjugation to interleukin 4 containing mutated cysteine residues produces interleukin4-toxin conjugates with improved binding and activity[J].Biochemistry,1994,33(38):11637-11644.
[38]Pan C,Roczniak S,Greve J,et al.Modified IL-4 mutein receptor antagonists:AU,2004270638A[P].2010-10-07.
[39]Duppatla V1,Gjorgjevikj M,Schmitz W,et al.IL-4 analogues with sitespecific chemical modification at position 121 inhibit IL-4 and IL-13biological activities[J].Bioconjugate Chem,2014,25(1):52-62.
[40]Hodges M R,Castelloe E,Chen A,et al.Randomized,double-blind,placebo controlled first in human study of inhaled AIR645,an IL-4Rαoligonucleotide,in healthy volunteers[EB/OL].(2009-05-15)[2018-12-20].https://doi.org/10.1164/ajrccm-conference.2009.179.1_MeetingAbstracts.A3640.
[41]Miklossy G,Hilliard T S,Turkson J.Therapeutic modulators of STATsignalling for human diseases[J].Nat Rev Drug Discov,2013,12(8):611-629.
[42]U.S.National Library of Medicine.NCT03722407[EB/OL].(2019-03-15)[2019-04-09].https://clinicaltrials.gov/ct2/show/NCT03722407?ter m=NCT03722407&rank=1.
[43]Aaronson D S,Horvath C M.A road map for those who don’t know JAK-STAT[J].Science,2002,296(5573):1653-1655.
[44]Junttila I S,Creusot R J,Moraga I,et al.Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines[J].Nat Chem Biol,2012,8(12):990-998.
[45]Medicenna Therapeutics Inc.MDNA57[EB/OL].(2014-07-13)[2019-04-09].https://www.medicenna.com/our-pipeline/empoweredcytokines/mdna57/.
[46]Roth F,Delf A C,Vella J L,et al.Aptamer-mediated blockade of IL-4Rtriggers apoptosis of MDSCs and limits tumor progression[J].Cancer Res,2012,72(6):1373-1383.
[47]Srabovici N,Mujagic Z,Mujanovic-Mustedanagic J,et al.Interleukin13 expression in the primary breast cancer tumor tissue[J].Biochem Med(Zagreb),2011,21(2):131-138.
[2]Siegel R L,Miller K D,Jemal A.Cancer statistics,2015[J].CA Cancer J Clin,2015,65(1):5-29.
[3]Venmar K T,Kimmel D W,Cliffel D E,et al.IL4 receptorαmediates enhanced glucose and glutamine metabolism to support breast cancer growth[J].Biochim Biophys Acta,2015,1853(5):1219-1228.
[4]Liang H E,Reinhardt R L,Bando J K,et al.Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity[J].Nat Immunol,2011,13(1):58-66.
[5]Wijesundara D K,Tscharke D C,Jackson R J,et al.Reduced interleukin-4 receptorαexpression on CD8+T cells correlates with higher quality anti-viral immunity[J].PLoS One,2013,8(1):e55788.Doi:10.1371/journal.pone.0055788.
[6]Wijesundara D K,Jackson R J,Tscharke D C,et al.IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8+T cell avidity following HIV-1 recombinant pox viral vaccination[J].Vaccine,2013,31(41):4548-4555.
[7]Mirchandani A S,Besnard A G,Yip E,et al.Type 2 innate lymphoid cells drive CD4+Th2 cell responses[J].J Immunol,2014,192(5):2442-2448.
[8]VanDyken S J,Mohapatra A,Nussbaum J C,et al.Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 andγδT cells[J].Immunity,2014,40(3):414-424.
[9]Kim M,Lim S J,Oidovsambuu S,et al.Gnetin H isolated from paeonia anomala inhibits FcεRI-mediated mast cell signaling and degranulation[J].J Ethnopharmacol,2014,154(3):798-806.
[10]Burks A W,Tang M,Sicherer S,et al.ICON:food allergy[J].J Allergy Clin Immunol,2012,129(4):906-920.
[11]Lee Y J,Holzapfel K L,Zhu J,et al.Steady-state production of IL-4modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells[J].Nat Immunol,2013,14(11):1146-1154.
[12]Vijayanand P,Seumois G,Simpson L J,et al.Interleukin-4 production by follicular helper T cells requires the conserved IL4 enhancer hypersensitivity site[J].Immunity,2012,36(2):175-187.
[13]Naz S,Baigg N,Khalil R,et al.Characterization of cryptic allosteric site at IL-4Rα:new paradigm towards IL-4/IL-4R inhibition[J].Int JBiol Macromol,2019,123:239-245.
[14]Passalacqua G,Mincarini M,Colombo D,et al.IL-13 and idiopathic pulmonary fibrosis:possible links and new therapeutic strategies[J].Pulm Pharmacol Ther,2017,45:95-100.
[15]U.S.National Library of Medicine.Interleukin-4 PE38KDEL[EB/OL].(2013-07-13)[2018-12-01].https://clinicaltrials.gov/ct2/show/NCT00039052?term=Interleukin-4+PE38KDEL&rank=1.
[16]Gandhi H,Worch R,Kurgonaite K,et al.Dynamics and interaction of interleukin-4 receptor subunits in living cells[J].Biophys J,2014,107(11):2515-2527.
[17]Porter H A,Perry A,Kingsley C,et al.IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy,while IRS2 is highly expressed in invasive breast tumors[J].Cancer Lett,2013,338(2):239-248.
[18]Yan X,Li W,Pan L,et al.Lewis lung cancer cells promote SIGNR1(CD209b)-mediated macrophages polarization induced by IL-4to facilitate immune evasion[J].J Cell Biochem,2016,117(5):1158-1166.
[19]Nappo G,Handle F,Santer F R,et al.The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling[J].Oncogenesis,2017,6(5):e342.Doi:10.1038/oncsis.2017.23.
[20]Djaldetti M,Bessler H.Modulators affecting the immune dialogue between human immune and colon cancer cells[J].World J Gastrointest Oncol,2014,6(5):129-138.
[21]Li B H,Xu S B,Li F,et al.Stat6 activity-related Th2 cytokine profile and tumor growth advantage of human colorectal cancer cells in vitro and in vivo[J].Cell Signal,2012,24(3):718-725.
[22]Leon-Cabrera S A,Molina-Guzman E,Delgado-Ramirez Y G,et al.Lack of STAT6 attenuates inflammation and drives protection against early steps of colitis-associated colon cancer[J].Cancer Immunol Res,2017,5(5):385-396.
[23]Guo C,Ouyang Y,Cai J,et al.High expression of IL-4R enhances proliferation and invasion of hepatocellular carcinoma cells[J].Int JBiol Markers,2017,32(4):e384-e390.
[24]Li G,Kikuchi K,Radka M,et al.IL-4 receptor blockade abrogates satellite cell:rhabdomyosarcoma fusion and prevents tumor establishment[J].Stem Cells,2013,31(11):2304-2312.
[25]Barik S,Cattin-Roy A N,Miller M M,et al.IL-4 and IL-13 guide early thymic progenitors to mature toward dendritic cells[J].J Immunol,2018,201(10):2947-2958.
[26]Oh C K,Geba G P,Molfino N.Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma[J].Eur Respir Rev,2010,19(115):46-54.
[27]Delgoffe G M,Kole T P,Zheng Y,et al.The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment[J].Immunity,2009,30(6):832-844.
[28]Gandhi N A,Bennett B L,Graham N M,et al.Targeting key proximal drivers of type 2 inflammation in disease[J].Nat Rev Drug Discov,2016,15(1):35-50.
[29]Bagnasco D,Ferrando M,Varricchi G,et al.A critical evaluation of anti-IL-13 and anti-IL-4 strategies in severe asthma[J].Int Arch Allergy Immunol,2016,170(2):122-131.
[30]Hamilton M J,Bosiljcic M,Lepard N E,et al.Macrophages are more potent immune suppressors ex vivo than immature myeloid-derived suppressor cells induced by metastatic murine mammary carcinomas[J].J Immunol,2014,192(1):512-522.
[31]Marvel D,Gabrilovich D I.Myeloid-derived suppressor cells in the tumor microenvironment:expect the unexpected[J].J Clin Invest,2015,125(9):3356-3364.
[32]Tanaka T.Flavonoids for allergic diseases:present evidence and future perspective[J].Curr Pharm Des,2014,20(6):879-885.
[33]Cai J,Zhao X L,Liu A W,et al.Apigenin inhibits hepatoma cell growth through alteration of gene expression patterns[J].Phytomedicine,2011,18(5):366-373.
[34]Xu X,Zheng Y,Zhang X,et al.Efficacy and safety of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults[J].Oncotarget,2017,8(65):108480-108491.
[35]Agrawal S,Townley R G.Role of periostin,FENO,IL-13,lebrikzumab,other IL-13 antagonist and dual IL-4/IL-13 antagonist in asthma[J].Expert Opin Biol Ther,2014,14(2):165-181.
[36]Tomkinson A,Tepper J,Morton M,et al.Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma[J].Allergy,2010,65(1):69-77.
[37]Kreitman R J,Puri R K,Leland P,et al.Site-specific conjugation to interleukin 4 containing mutated cysteine residues produces interleukin4-toxin conjugates with improved binding and activity[J].Biochemistry,1994,33(38):11637-11644.
[38]Pan C,Roczniak S,Greve J,et al.Modified IL-4 mutein receptor antagonists:AU,2004270638A[P].2010-10-07.
[39]Duppatla V1,Gjorgjevikj M,Schmitz W,et al.IL-4 analogues with sitespecific chemical modification at position 121 inhibit IL-4 and IL-13biological activities[J].Bioconjugate Chem,2014,25(1):52-62.
[40]Hodges M R,Castelloe E,Chen A,et al.Randomized,double-blind,placebo controlled first in human study of inhaled AIR645,an IL-4Rαoligonucleotide,in healthy volunteers[EB/OL].(2009-05-15)[2018-12-20].https://doi.org/10.1164/ajrccm-conference.2009.179.1_MeetingAbstracts.A3640.
[41]Miklossy G,Hilliard T S,Turkson J.Therapeutic modulators of STATsignalling for human diseases[J].Nat Rev Drug Discov,2013,12(8):611-629.
[42]U.S.National Library of Medicine.NCT03722407[EB/OL].(2019-03-15)[2019-04-09].https://clinicaltrials.gov/ct2/show/NCT03722407?ter m=NCT03722407&rank=1.
[43]Aaronson D S,Horvath C M.A road map for those who don’t know JAK-STAT[J].Science,2002,296(5573):1653-1655.
[44]Junttila I S,Creusot R J,Moraga I,et al.Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines[J].Nat Chem Biol,2012,8(12):990-998.
[45]Medicenna Therapeutics Inc.MDNA57[EB/OL].(2014-07-13)[2019-04-09].https://www.medicenna.com/our-pipeline/empoweredcytokines/mdna57/.
[46]Roth F,Delf A C,Vella J L,et al.Aptamer-mediated blockade of IL-4Rtriggers apoptosis of MDSCs and limits tumor progression[J].Cancer Res,2012,72(6):1373-1383.
[47]Srabovici N,Mujagic Z,Mujanovic-Mustedanagic J,et al.Interleukin13 expression in the primary breast cancer tumor tissue[J].Biochem Med(Zagreb),2011,21(2):131-138.