【《PD-L1与肿瘤免疫治疗研究文献综述》2600字】

PD-L1与肿瘤免疫治疗研究文献综述目录TOC\o"1-3"\h\u17097PD-L1与肿瘤免疫治疗研究文献综述 1167061.1PD-1/PD-L1监测点 138011.2PD-L1表达调控机制 2131901.3PD-L1抗体治疗现状 41.1PD-1/PD-L1监测点免疫逃逸对于癌症的发生、发展和治疗至关重要。基于T细胞的免疫系统可识别树突状细胞所携带的特异性抗原从而使T细胞能够进入人体的特定位点杀死异常细胞ADDINEN.CITE<EndNote><Cite><Author>Cortinovis</Author><Year>2016</Year><RecNum>216</RecNum><DisplayText><styleface="superscript">[25]</style></DisplayText><record><rec-number>216</rec-number><foreign-keys><keyapp="EN"db-id="0v2rd9evm529trepf0a5tfpu9v9ap2tf5zd2"timestamp="1615002607">216</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Cortinovis,D.L.</author><author>Canova,S.</author><author>Abbate,M.</author><author>Colonese,F.</author><author>Bidoli,P.</author></authors></contributors><auth-address>SCOncologiaMedica,OspedaleSanGerardo,Monza,Italy.</auth-address><titles><title>FocusonNivolumabinNSCLC</title><secondary-title>FrontMed(Lausanne)</secondary-title><alt-title>Frontiersinmedicine</alt-title></titles><periodical><full-title>FrontMed(Lausanne)</full-title><abbr-1>Frontiersinmedicine</abbr-1></periodical><alt-periodical><full-title>FrontMed(Lausanne)</full-title><abbr-1>Frontiersinmedicine</abbr-1></alt-periodical><pages>67</pages><volume>3</volume><edition>2016/12/27</edition><keywords><keyword>Nsclc</keyword><keyword>Pd-1</keyword><keyword>Pdl1</keyword><keyword>checkpointinhibitors</keyword><keyword>immunotherapy</keyword><keyword>nivolumab</keyword></keywords><dates><year>2016</year></dates><isbn>2296-858X(Print) 2296-858x</isbn><accession-num>28018902</accession-num><urls></urls><custom2>PMC5153403</custom2><electronic-resource-num>10.3389/fmed.2016.00067</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[25]。而抗原特异性T细胞的激活和增殖受免疫监测点的控制ADDINEN.CITEADDINEN.CITE.DATA[26,27]。在所有免疫监测点中，PD-1/PD-L1途径因其在许多恶性肿瘤中的作用而备受关注。PD-1是一种I型跨膜糖蛋白，属于CD28家族ADDINEN.CITEADDINEN.CITE.DATA[28]，主要在记忆T细胞上表达ADDINEN.CITEADDINEN.CITE.DATA[29,30]。PD-1有PD-L1和PD-L2两个配体，它们都是跨膜蛋白B7家族的成员ADDINEN.CITEADDINEN.CITE.DATA[31]。编码PD-L1蛋白的CD274基因包含七个外显子，位于人9号染色体ADDINEN.CITE<EndNote><Cite><Author>Keir</Author><Year>2008</Year><RecNum>70</RecNum><DisplayText><styleface="superscript">[32]</style></DisplayText><record><rec-number>70</rec-number><foreign-keys><keyapp="EN"db-id="0v2rd9evm529trepf0a5tfpu9v9ap2tf5zd2"timestamp="1606132392">70</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Keir,M.E.</author><author>Butte,M.J.</author><author>Freeman,G.J.</author><author>Sharpe,A.H.</author></authors></contributors><auth-address>DepartmentofPathology,HarvardMedicalSchoolandBrighamandWomen'sHospital,Boston,Massachusetts02115-5727,USA.</auth-address><titles><title>PD-1anditsligandsintoleranceandimmunity</title><secondary-title>AnnuRevImmunol</secondary-title><alt-title>Annualreviewofimmunology</alt-title></titles><periodical><full-title>AnnuRevImmunol</full-title><abbr-1>Annualreviewofimmunology</abbr-1></periodical><alt-periodical><full-title>AnnuRevImmunol</full-title><abbr-1>Annualreviewofimmunology</abbr-1></alt-periodical><pages>677-704</pages><volume>26</volume><edition>2008/01/05</edition><keywords><keyword>Animals</keyword><keyword>Antigens,CD/*physiology</keyword><keyword>ApoptosisRegulatoryProteins/*physiology</keyword><keyword>B7-1Antigen/physiology</keyword><keyword>B7-H1Antigen</keyword><keyword>Humans</keyword><keyword>Immunity/*physiology</keyword><keyword>Ligands</keyword><keyword>Models,Immunological</keyword><keyword>ProgrammedCellDeath1Receptor</keyword><keyword>SelfTolerance/*physiology</keyword></keywords><dates><year>2008</year></dates><isbn>0732-0582(Print) 0732-0582</isbn><accession-num>18173375</accession-num><urls></urls><electronic-resource-num>10.1146/annurev.immunol.26.021607.090331</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[32]，每个外显子编码PD-L1蛋白的不同部分，包含胞内区、跨膜区和两个胞外区（IgC和IgV）ADDINEN.CITEADDINEN.CITE.DATA[31,33]，（如图1所示）。PD-L1可在多种肿瘤细胞表面表达ADDINEN.CITEADDINEN.CITE.DATA[34,35]，也可在肿瘤浸润T细胞、B细胞、单核细胞、抗原呈递细胞和上皮细胞中表达ADDINEN.CITE<EndNote><Cite><Author>Sharpe</Author><Year>2007</Year><RecNum>217</RecNum><DisplayText><styleface="superscript">[36]</style></DisplayText><record><rec-number>217</rec-number><foreign-keys><keyapp="EN"db-id="0v2rd9evm529trepf0a5tfpu9v9ap2tf5zd2"timestamp="1615003710">217</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sharpe,A.H.</author><author>Wherry,E.J.</author><author>Ahmed,R.</author><author>Freeman,G.J.</author></authors></contributors><auth-address>DepartmentofPathology,HarvardMedicalSchoolandBrighamandWomen'sHospital,Boston,Massachusetts02115,USA.arlene_sharpe@</auth-address><titles><title>Thefunctionofprogrammedcelldeath1anditsligandsinregulatingautoimmunityandinfection</title><secondary-title>NatImmunol</secondary-title><alt-title>Natureimmunology</alt-title></titles><periodical><full-title>NatImmunol</full-title><abbr-1>Natureimmunology</abbr-1></periodical><alt-periodical><full-title>NatImmunol</full-title><abbr-1>Natureimmunology</abbr-1></alt-periodical><pages>239-45</pages><volume>8</volume><number>3</number><edition>2007/02/17</edition><keywords><keyword>Animals</keyword><keyword>Antigens,CD/genetics/*immunology/metabolism</keyword><keyword>*Autoimmunity</keyword><keyword>B7-H1Antigen</keyword><keyword>CommunicableDiseases/*immunology</keyword><keyword>Humans</keyword><keyword>ImmuneTolerance</keyword><keyword>IntercellularSignalingPeptidesandProteins/*immunology/metabolism</keyword><keyword>LymphocyteActivation/immunology</keyword><keyword>*Models,Immunological</keyword><keyword>ProgrammedCellDeath1Ligand2Protein</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1529-2908(Print) 1529-2908</isbn><accession-num>17304234</accession-num><urls></urls><electronic-resource-num>10.1038/ni1443</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[36]，（如图2所示）。T细胞表面的PD-1与其配体PD-L1或PD-L2结合可诱导PD-1构象变化，从而导致PD-1的胞内免疫受体酪氨酸抑制基序（ITIM）和免疫受体酪氨酸转换基序（ITSM）被SCr家族激酶磷酸化。这些磷酸化的酪氨酸基序随后募集SHP-1和SHP-2蛋白酪氨酸磷酸酶，以减弱T细胞激活信号，抑制T细胞的增殖和功能ADDINEN.CITEADDINEN.CITE.DATA[37,38]，并促进CD4+T细胞分化为Foxp3+调节性T细胞，诱导其耗竭ADDINEN.CITEADDINEN.CITE.DATA[39]。图1PD-L1DNA，mRNA，蛋白质结构。（图片引自：AnnalsofOncology,2016,27(3):409.）图2PD-L1和PD-1途径的作用机制。PD-L1阳性细胞与T细胞接触可能诱导T细胞凋亡，无反应，功能衰竭或IL-10产生。（图片引自：SciTranslMed.2016March2;8(328):328rv4.doi:10.1126/scitranslmed.aad7118.）1.2PD-L1表达调控机制由于肿瘤微环境的复杂多样，PD-L1的表达受多种因素调节。（1）PD-L1表达受基因的影响。在霍奇金淋巴瘤和纵隔大B细胞淋巴瘤中，染色体9的扩增与PD-L1的高表达相关。此外，由于JAK激酶也位于9号染色体，其扩增也可通过增强IFN-γ信号通路上调PD-L1的表达ADDINEN.CITEADDINEN.CITE.DATA[40]。同时，PD-L1基因的表达受其3，UTR区域调控，PD-L13，UTR的缺失会使PD-L1的mRNA更稳定ADDINEN.CITEADDINEN.CITE.DATA[41]。（2）PD-L1的表达可由多种细胞因子诱导或维持ADDINEN.CITEADDINEN.CITE.DATA[35,42-44]。人体内许多细胞因子均可在不同的环境中以不同的方式调控PD-L1的表达，但其中最主要的是IFN-γ。IFN-γ是一种促炎细胞因子，T细胞活化后可产生大量IFN-γ。研究表明在多种肿瘤、健康组织和免疫细胞中IFN-γ可调节PD-L1的表达ADDINEN.CITEADDINEN.CITE.DATA[35]。IFN-γ与其受体结合后通过经典的JAK-STAT信号传导，从而诱导干扰素反应因子（IRF）的表达ADDINEN.CITEADDINEN.CITE.DATA[45]。其中，IRF1在IFN-γ介导的PD-L1上调中起核心作用ADDINEN.CITEADDINEN.CITE.DATA[46]，（如图3所示）。此外，其他的可溶性因子也会调控PD-L1表达，如在单核细胞、巨噬细胞和膀胱癌细胞中脂多糖均可通过TLR4诱导NF-κB活化从而诱导I型干扰素的产生，继而上调PD-L1的表达ADDINEN.CITEADDINEN.CITE.DATA[47]；IL-1α通过p65驱动PD-L1蛋白表达；IL-27可通过激活STAT1和STAT3显著上调PD-L1的表达等ADDINEN.CITEADDINEN.CITE.DATA[48-51]。（3）异常致癌信号影响PD-L1表达。影响细胞存活、增殖和分化的主要信号通路的改变是癌症发生发展的关键ADDINEN.CITE<EndNote><Cite><Author>Hanahan</Author><Year>2011</Year><RecNum>221</RecNum><DisplayText><styleface="superscript">[52]</style></DisplayText><record><rec-number>221</rec-number><foreign-keys><keyapp="EN"db-id="0v2rd9evm529trepf0a5tfpu9v9ap2tf5zd2"timestamp="1615023186">221</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hanahan,D.</author><author>Weinberg,R.A.</author></authors></contributors><auth-address>TheSwissInstituteforExperimentalCancerResearch(ISREC),SchoolofLifeSciences,EPFL,LausanneCH-1015,Switzerland.dh@epfl.ch</auth-address><titles><title>Hallmarksofcancer:thenextgeneration</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>646-74</pages><volume>144</volume><number>5</number><edition>2011/03/08</edition><keywords><keyword>Animals</keyword><keyword>GenomicInstability</keyword><keyword>Humans</keyword><keyword>NeoplasmInvasiveness</keyword><keyword>Neoplasms/metabolism/*pathology/*physiopathology</keyword><keyword>SignalTransduction</keyword><keyword>StromalCells/pathology</keyword></keywords><dates><year>2011</year><pub-dates><date>Mar4</date></pub-dates></dates><isbn>0092-8674</isbn><accession-num>21376230</accession-num><urls></urls><electronic-resource-num>10.1016/j.cell.2011.02.013</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[52]。转录因子、信号通路的效应子和上游受体发生改变的致癌信号均可影响PD-L1表达。①在大约70％的人类癌症中可见MYC基因的高表达ADDINEN.CITE<EndNote><Cite><Author>Dang</Author><Year>2012</Year><RecNum>222</RecNum><DisplayText><styleface="superscript">[53]</style></DisplayText><record><rec-number>222</rec-number><foreign-keys><keyapp="EN"db-id="0v2rd9evm529trepf0a5tfpu9v9ap2tf5zd2"timestamp="1615023552">222</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Dang,C.V.</author></authors></contributors><auth-address>DivisionofHematology-Oncology,DepartmentofMedicine,AbramsonCancerCenter,AbramsonFamilyCancerResearchInstitute,PerelmanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,PA19104,USA.dangvchi@</auth-address><titles><title>MYConthepathtocancer</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>22-35</pages><volume>149</volume><number>1</number><edition>2012/04/03</edition><keywords><keyword>Animals</keyword><keyword>BasicHelix-Loop-HelixLeucineZipperTranscriptionFactors/metabolism</keyword><keyword>CellTransformation,Neoplastic</keyword><keyword>GeneExpressionRegulation,Neoplastic</keyword><keyword>Genes,myc</keyword><keyword>Humans</keyword><keyword>Neoplasms/genetics/*metabolism/therapy</keyword><keyword>Proto-OncogeneProteinsc-myc/genetics/*metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar30</date></pub-dates></dates><isbn>0092-8674(Print) 0092-8674</isbn><accession-num>22464321</accession-num><urls></urls><custom2>PMC3345192</custom2><custom6>NIHMS364872</custom6><electronic-resource-num>10.1016/j.cell.2012.03.003</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[53]。MYC可与PD-L1启动子结合，且MYC的失活会导致多种肿瘤细胞（包括黑素瘤、非小细胞肺癌、白血病、淋巴瘤和肝癌）中PD-L1表达降低，表明MYC可直接调控PD-L1的转录水平ADDINEN.CITEADDINEN.CITE.DATA[54,55]。②缺氧是大多数肿瘤发展中的关键特征。肿瘤通过激活缺氧诱导因子（HIF）来应对氧气缺乏。在乳腺癌和前列腺癌中，HIF-1α与PD-L1启动子区域中的缺氧反应元件（HRE）发生物理结合，进而上调PD-L1表达ADDINEN.CITEADDINEN.CITE.DATA[56,57]。③STAT3是一种转录因子，可促进细胞存活、增殖和转移。它在多种生长因子和细胞因子下游发挥作用，并发现在多种癌症中具有活性ADDINEN.CITEADDINEN.CITE.DATA[58]。研究表明，在人淋巴瘤和HNSCC细胞中STAT3可直接作用于PD-L1的启动子，从而增加其表达ADDINEN.CITEADDINEN.CITE.DATA[54,59]。④在癌症中，NF-κB可被炎症微环境中产生的致癌突变和细胞因子激活。据报道，抑制NF-κB通路可导致人NK/T细胞淋巴瘤、黑色素瘤细胞和原代单核细胞中PD-L1表达降低ADDINEN.CITEADDINEN.CITE.DATA[60,61]。同时p65（NF-κB的亚基）与非小细胞肺癌细胞和乳腺癌细胞中PD-L1启动子结合，表明NF-κB可以直接调节PD-L1的转录ADDINEN.CITEADDINEN.CITE.DATA[62]。⑤CDK5是一种丝氨酸-苏氨酸激酶，其可抑制IRF2BP2的翻译后修饰，影响IRF2的稳定性，从而导致IRF1介导的PD-L1转录上调ADDINEN.CITEADDINEN.CITE.DATA[63]。⑥磷脂酰肌醇3-激酶（PI3K）信号通路可影响癌细胞的存活、增殖、代谢和迁移等。位于PI3K下游的AKT-mTOR级联也可被I型和II型干扰素激活，并控制相关mRNA翻译，这表明干扰素受体信号通路和AKT-mTOR信号通路间存在关联ADDINEN.CITEADDINEN.CITE.DATA[64]，（如图3所示），因此抑制PI3K/AKT信号可能会影响IFN-γ诱导的PD-L1表达。此外，在肺癌、乳腺癌和黑色素瘤中PI3K/AKT信号也可不依赖于IFN-γ通路调控PD-L1表达ADDINEN.CITEADDINEN.CITE.DATA[65,66]。⑦在多数人类癌症中MEK-ERK途径显示被激活ADDINEN.CITE<EndNote><Cite><Author>Roberts</Author><Year>2007</Year><RecNum>235</RecNum><DisplayText><styleface="superscript">[67]</style></DisplayText><record><rec-number>235</rec-number><foreign-keys><keyapp="EN"db-id="0v2rd9evm529trepf0a5tfpu9v9ap2tf5zd2"timestamp="1615026762">235</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Roberts,P.J.</author><author>Der,C.J.</author></authors></contributors><auth-address>DivisionofPharmacotherapyandExperimentalTherapeutics,LinebergerComprehensiveCancerCenter,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC27599-7295,USA.</auth-address><titles><title>TargetingtheRaf-MEK-ERKmitogen-activatedproteinkinasecascadeforthetreatmentofcancer</title><secondary-title>Oncogene</secondary-title><alt-title>Oncogene</alt-title></titles><periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></periodical><alt-periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></alt-periodical><pages>3291-310</pages><volume>26</volume><number>22</number><edition>2007/05/15</edition><keywords><keyword>Animals</keyword><keyword>DrugDeliverySystems/*methods</keyword><keyword>ExtracellularSignal-RegulatedMAPKinases/*antagonists&inhibitors/physiology</keyword><keyword>Humans</keyword><keyword>MAPKinaseKinaseKinases/*antagonists&inhibitors/physiology</keyword><keyword>MAPKinaseSignalingSystem/*drugeffects/physiology</keyword><keyword>Neoplasms/*drugtherapy/*enzymology/genetics</keyword><keyword>rafKinases/*antagonists&inhibitors/genetics/physiology</keyword></keywords><dates><year>2007</year><pub-dates><date>May14</date></pub-dates></dates><isbn>0950-9232(Print) 0950-9232</isbn><accession-num>17496923</accession-num><urls></urls><electronic-resource-num>10.1038/sj.onc.1210422</electronic-resource