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DOI | 10.1038/s41586-020-2229-5 |
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I | |
Waszak, Sebastian M.1; Robinson, Giles W.2; Gudenas, Brian L.3; Smith, Kyle S.3; Forget, Antoine4; Kojic, Marija5,5; Garcia-Lopez, Jesus3; Hadley, Jennifer3; Hamilton, Kayla V.6; Indersie, Emilie4; Buchhalter, Ivo7; Kerssemakers, Jules7; Jager, Natalie8,9; Sharma, Tanvi8,9; Rausch, Tobias1; Kool, Marcel8,9,10; Sturm, Dominik8,11; Jones, David T. W.8,11; Vasilyeva, Aksana1,12; Tatevossian, Ruth G.13,14; Neale, Geoffrey14; Lombard, Berangere14; Loew, Damarys14; Nakitandwe, Joy13,14; Rusch, Michael16; Bowers, Daniel C.17; Bendel, Anne18; Partap, Sonia19; Chintagumpala, Murali20; Crawford, John21,22,23; Gottardo, Nicholas G.24,24; Smith, Amy26; Dufour, Christelle27; Rutkowski, Stefan28; Eggen, Tone29; Wesenberg, Finn30; Kjaerheim, Kristina30; Feychting, Maria31; Lannering, Birgitta32; Schuz, Joachim33; Johansen, Christoffer34,34; Andersen, Tina V.36; Roosli, Martin37; Kuehni, Claudia E.37,38; Grotzer, Michael39; Remke, Marc40; Puget, Stephanie41; Pajtler, Kristian W.8,9,42; Milde, Till8,42,43; Witt, Olaf8,42,43; Ryzhova, Marina44; Korshunov, Andrey44,46; Orr, Brent A.13,14; Ellison, David W.13,14; Brugieres, Laurence27; Lichter, Peter47; Nichols, Kim E.6; Gajjar, Amar2; Wainwright, Brandon J.5,5; Ayrault, Olivier4; Korbel, Jan O.1; Northcott, Paul A.3; Pfister, Stefan M.8,9,42 | |
2020-04-16 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2020 |
卷号 | 581期号:7806页码:100-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; England |
英文关键词 | Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1-3). However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found(5) despite the frequent downregulation of MHC-I expression(6-8). Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC. Inhibition of the autophagy-lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8(+) T cells. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000528161900005 |
WOS关键词 | DENDRITIC CELLS ; EXPRESSION ; REVEALS ; PROGRESSION ; METABOLISM ; RESPONSES ; TUMORS ; GROWTH ; FLUX |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/281238 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.European Mol Biol Lab EMBL, Genome Biol Unit, Heidelberg, Germany; 2.St Jude Childrens Res Hosp, Dept Oncol, Div Neurooncol, 332 N Lauderdale St, Memphis, TN 38105 USA; 3.St Jude Childrens Res Hosp, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA; 4.Univ Paris Saclay, Univ Paris Sud, CNRS, INSERM,UMR 3347,U1021, Orsay, France; 5.Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia; 6.St Jude Childrens Res Hosp, Div Canc Predisposit, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA; 7.German Canc Res Ctr, Omics IT & Data Management Core Facil W610, Heidelberg, Germany; 8.Hopp Childrens Canc Ctr Heidelberg KiTZ, Heidelberg, Germany; 9.German Canc Res Ctr, German Consortium Translat Canc Res DKTK, Div Pediat Neurooncol, Heidelberg, Germany; 10.Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands; 11.German Canc Res Ctr, Pediat Glioma Res Grp, Heidelberg, Germany; 12.St Jude Childrens Res Hosp, Canc Ctr Adm, 332 N Lauderdale St, Memphis, TN 38105 USA; 13.St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA; 14.St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA; 15.PSL Res Univ, Lab Spectrometrie Masse Proteom, Ctr Rech, Inst Curie, Paris, France; 16.St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA; 17.Univ Texas Southwestern Med Sch, Div Pediat Hematol Oncol, Dallas, TX USA; 18.Childrens Hosp & Clin Minnesota, Dept Pediat Hematol & Oncol, St Paul, MN USA; 19.Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA; 20.Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA; 21.Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA; 22.Rady Childrens Hosp, San Diego, CA USA; 23.Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA; 24.Perth Childrens Hosp, Dept Paediat & Adolescent Oncol Haematol, Perth, WA, Australia; 25.Telethon Kids Inst, Brain Tumour Res Programme, Perth, WA, Australia; 26.Arnold Palmer Hosp Ctr Childrens Canc, Orlando, FL USA; 27.Univ Paris Saclay, Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France; 28.Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany; 29.Canc Registry Norway, Oslo, Norway; 30.Inst Populat Based Canc Res, Canc Registry Norway, Dept Res, Oslo, Norway; 31.Karolinska Inst, Inst Environm Med, Stockholm, Sweden; 32.Univ Gothenburg, Queen Silvia Childrens Hosp, Dept Pediat, Gothenburg, Sweden; 33.Int Agcy Res Canc IARC, Sect Environm & Radiat, Lyon, France; 34.Univ Copenhagen, Rigshosp, Finsen Ctr, Oncol Clin, Copenhagen, Denmark; 35.Danish Canc Soc, Res Ctr, Copenhagen, Denmark; 36.Univ Basel, Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland; 37.Univ Bern, Inst Social & Prevent Med, Swiss Childhood Canc Registry, Bern, Switzerland; 38.Univ Childrens Hosp, Dept Paediat Haematol & Oncol, Bern, Switzerland; 39.Univ Childrens Hosp Zurich, Zurich, Switzerland; 40.Univ Hosp Dusseldorf, Fac Med, Dept Pediat Oncol Hematol & Clin Immunol, Dusseldorf, Germany; 41.Univ Paris, Necker Hosp, Dept Pediat Neurosurg, Paris, France; 42.Heidelberg Univ Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany; 43.German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol, Heidelberg, Germany; 44.Burdenko Neurosurg Inst, Dept Neuropathol, Moscow, Russia; 45.German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany; 46.Univ Hosp, Dept Neuropathol, Heidelberg, Germany; 47.German Canc Res Ctr Heidelberg DKFZ, German Consortium Translat Canc Res DKTK, Div Mol Genet, Heidelberg, Germany |
推荐引用方式 GB/T 7714 | Waszak, Sebastian M.,Robinson, Giles W.,Gudenas, Brian L.,et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I[J]. NATURE,2020,581(7806):100-+. |
APA | Waszak, Sebastian M..,Robinson, Giles W..,Gudenas, Brian L..,Smith, Kyle S..,Forget, Antoine.,...&Pfister, Stefan M..(2020).Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.NATURE,581(7806),100-+. |
MLA | Waszak, Sebastian M.,et al."Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I".NATURE 581.7806(2020):100-+. |
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