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Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I 期刊论文
NATURE, 2020, 581 (7806) : 100-+
作者:  Waszak, Sebastian M.;  Robinson, Giles W.;  Gudenas, Brian L.;  Smith, Kyle S.;  Forget, Antoine;  Kojic, Marija;  Garcia-Lopez, Jesus;  Hadley, Jennifer;  Hamilton, Kayla V.;  Indersie, Emilie;  Buchhalter, Ivo;  Kerssemakers, Jules;  Jager, Natalie;  Sharma, Tanvi;  Rausch, Tobias;  Kool, Marcel;  Sturm, Dominik;  Jones, David T. W.;  Vasilyeva, Aksana;  Tatevossian, Ruth G.;  Neale, Geoffrey;  Lombard, Berangere;  Loew, Damarys;  Nakitandwe, Joy;  Rusch, Michael;  Bowers, Daniel C.;  Bendel, Anne;  Partap, Sonia;  Chintagumpala, Murali;  Crawford, John;  Gottardo, Nicholas G.;  Smith, Amy;  Dufour, Christelle;  Rutkowski, Stefan;  Eggen, Tone;  Wesenberg, Finn;  Kjaerheim, Kristina;  Feychting, Maria;  Lannering, Birgitta;  Schuz, Joachim;  Johansen, Christoffer;  Andersen, Tina V.;  Roosli, Martin;  Kuehni, Claudia E.;  Grotzer, Michael;  Remke, Marc;  Puget, Stephanie;  Pajtler, Kristian W.;  Milde, Till;  Witt, Olaf;  Ryzhova, Marina;  Korshunov, Andrey;  Orr, Brent A.;  Ellison, David W.;  Brugieres, Laurence;  Lichter, Peter;  Nichols, Kim E.;  Gajjar, Amar;  Wainwright, Brandon J.;  Ayrault, Olivier;  Korbel, Jan O.;  Northcott, Paul A.;  Pfister, Stefan M.
收藏  |  浏览/下载:38/0  |  提交时间:2020/07/03

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.


  
Megahertz serial crystallography 期刊论文
NATURE COMMUNICATIONS, 2018, 9
作者:  Wiedorn, Max O.;  Oberthuer, Dominik;  Bean, Richard;  Schubert, Robin;  Werner, Nadine;  Abbey, Brian;  Aepfelbacher, Martin;  Adriano, Luigi;  Allahgholi, Aschkan;  Al-Qudami, Nasser;  Andreasson, Jakob;  Aplin, Steve;  Awel, Salah;  Ayyer, Kartik;  Bajt, Sasa;  Barak, Imrich;  Bari, Sadia;  Bielecki, Johan;  Botha, Sabine;  Boukhelef, Djelloul;  Brehm, Wolfgang;  Brockhauser, Sandor;  Cheviakov, Igor;  Coleman, Matthew A.;  Cruz-Mazo, Francisco;  Danilevski, Cyril;  Darmanin, Connie;  Doak, R. Bruce;  Domaracky, Martin;  Doerner, Katerina;  Du, Yang;  Fangohr, Hans;  Fleckenstein, Holger;  Frank, Matthias;  Fromme, Petra;  Ganan-Calvo, Alfonso M.;  Gevorkov, Yaroslav;  Giewekemeyer, Klaus;  Ginn, Helen Mary;  Graafsma, Heinz;  Graceffa, Rita;  Greiffenberg, Dominic;  Gumprecht, Lars;  Goettlicher, Peter;  Hajdu, Janos;  Hauf, Steffen;  Heymann, Michael;  Holmes, Susannah;  Horke, Daniel A.;  Hunter, Mark S.;  Imlau, Siegfried;  Kaukher, Alexander;  Kim, Yoonhee;  Klyuev, Alexander;  Knoska, Juraj;  Kobe, Bostjan;  Kuhn, Manuela;  Kupitz, Christopher;  Kuepper, Jochen;  Lahey-Rudolph, Janine Mia;  Laurus, Torsten;  Le Cong, Karoline;  Letrun, Romain;  Xavier, P. Lourdu;  Maia, Luis;  Maia, Filipe R. N. C.;  Mariani, Valerio;  Messerschmidt, Marc;  Metz, Markus;  Mezza, Davide;  Michelat, Thomas;  Mills, Grant;  Monteiro, Diana C. F.;  Morgan, Andrew;  Muhlig, Kerstin;  Munke, Anna;  Muennich, Astrid;  Nette, Julia;  Nugent, Keith A.;  Nuguid, Theresa;  Orville, Allen M.;  Pandey, Suraj;  Pena, Gisel;  Villanueva-Perez, Pablo;  Poehlsen, Jennifer;  Previtali, Gianpietro;  Redecke, Lars;  Riekehr, Winnie Maria;  Rohde, Holger;  Round, Adam;  Safenreiter, Tatiana;  Sarrou, Iosifina;  Sato, Tokushi;  Schmidt, Marius;  Schmitt, Bernd;  Schoenherr, Robert;  Schulz, Joachim;  Sellberg, Jonas A.;  Seibert, M. Marvin;  Seuring, Carolin;  Shelby, Megan L.;  Shoeman, Robert L.;  Sikorski, Marcin;  Silenzi, Alessandro;  Stan, Claudiu A.;  Shi, Xintian;  Stern, Stephan;  Sztuk-Dambietz, Jola;  Szuba, Janusz;  Tolstikova, Aleksandra;  Trebbin, Martin;  Trunk, Ulrich;  Vagovic, Patrik;  Ve, Thomas;  Weinhausen, Britta;  White, Thomas A.;  Wrona, Krzysztof;  Xu, Chen;  Yefanov, Oleksandr;  Zatsepin, Nadia;  Zhang, Jiaguo;  Perbandt, Markus;  Mancuso, Adrian P.;  Betzel, Christian;  Chapman, Henry;  Barty, Anton
收藏  |  浏览/下载:25/0  |  提交时间:2019/11/27
Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation 期刊论文
SCIENCE, 2019, 365 (6455) : 825-+
作者:  Kim, Tae Hun;  Tsang, Brian;  Vernon, Robert M.;  Sonenberg, Nahum;  Kay, Lewis E.;  Forman-Kay, Julie D.
收藏  |  浏览/下载:6/0  |  提交时间:2019/11/27
Seasonal and Topographic Variations in Ecohydrological Separation Within a Small, Temperate, Snow-Influenced Catchmet 期刊论文
WATER RESOURCES RESEARCH, 2019, 55 (8) : 6417-6435
作者:  Knighton, James;  Souter-Kline, Valessa;  Volkman, Till;  Troch, Peter A.;  Kim, Minseok;  Harman, Ciaran;  Morris, Chelsea;  Buchanan, Brian;  Walter, M. Todd
收藏  |  浏览/下载:9/0  |  提交时间:2019/11/27
Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology 期刊论文
NATURE COMMUNICATIONS, 2019, 10
作者:  Plassais, Jocelyn;  Kim, Jaemin;  Davis, Brian W.;  Karyadi, Danielle M.;  Hogan, Andrew N.;  Harris, Alex C.;  Decker, Brennan;  Parker, Heidi G.;  Ostrander, Elaine A.
收藏  |  浏览/下载:7/0  |  提交时间:2019/11/27
Large-scale transcriptome-wide association study identifies new prostate cancer risk regions (vol 9, 4079, 2018) 期刊论文
NATURE COMMUNICATIONS, 2019, 10
作者:  Mancuso, Nicholas;  Gayther, Simon;  Gusev, Alexander;  Zheng, Wei;  Penney, Kathryn L.;  Kote-Jarai, Zsofia;  Eeles, Rosalind;  Freedman, Matthew;  Haiman, Christopher;  Pasaniuc, Bogdan;  Henderson, Brian E.;  Benlloch, Sara;  Schumacher, Fredrick R.;  Al Olama, Ali Amin;  Muir, Kenneth;  Berndt, Sonja I.;  Conti, David V.;  Wiklund, Fredrik;  Chanock, Stephen;  Stevens, Victoria L.;  Tangen, Catherine M.;  Batra, Jyotsna;  Clements, Judith;  Gronberg, Henrik;  Pashayan, Nora;  Schleutker, Johanna;  Albanes, Demetrius;  Weinstein, Stephanie;  Wolk, Alicja;  West, Catharine;  Mucci, Lorelei;  Cancel-Tassin, Geraldine;  Koutros, Stella;  Sorensen, Karina Dalsgaard;  Maehle, Lovise;  Neal, David E.;  Hamdy, Freddie C.;  Donovan, Jenny L.;  Travis, Ruth C.;  Hamilton, Robert J.;  Ingles, Sue Ann;  Rosenstein, Barry;  Lu, Yong-Jie;  Giles, Graham G.;  Kibel, Adam S.;  Vega, Ana;  Kogevinas, Manolis;  Park, Jong Y.;  Stanford, Janet L.;  Cybulski, Cezary;  Nordestgaard, Borge G.;  Brenner, Hermann;  Maier, Christiane;  Kim, Jeri;  John, Esther M.;  Teixeira, Manuel R.;  Neuhausen, Susan L.;  De Ruyck, Kim;  Razack, Azad;  Newcomb, Lisa F.;  Lessel, Davor;  Kaneva, Radka;  Usmani, Nawaid;  Claessens, Frank;  Townsend, Paul A.;  Gago-Dominguez, Manuela;  Roobol, Monique J.;  Menegaux, Florence;  Khaw, Kay-Tee;  Cannon-Albright, Lisa;  Pandha, Hardev;  Thibodeau, Stephen N.;  Hunter, David J.;  Kraft, Peter
收藏  |  浏览/下载:16/0  |  提交时间:2019/11/27
Coastal ecosystems on a tipping point: Global warming and parasitism combine to alter community structure and function 期刊论文
GLOBAL CHANGE BIOLOGY, 2018, 24 (9) : 4340-4356
作者:  Mouritsen, Kim N.;  Sorensen, Mikkel M.;  Poulin, Robert;  Fredensborg, Brian L.
收藏  |  浏览/下载:3/0  |  提交时间:2019/04/09
amphipod host community  climate change  Maritrema novaezealandensis  mesocosm experiment  microphallid trematode  parasite vulnerability  species diversity  species richness  temperature sensitivity  temperature-parasitism synergy  
Past and future global transformation of terrestrial ecosystems under climate change 期刊论文
SCIENCE, 2018, 361 (6405) : 920-923
作者:  Nolan, Connor;  Overpeck, Jonathan T.;  Allen, Judy R. M.;  Anderson, Patricia M.;  Betancourt, Julio L.;  Binney, Heather A.;  Brewer, Simon;  Bush, Mark B.;  Chase, Brian M.;  Cheddadi, Rachid;  Djamali, Morteza;  Dodson, John;  Edwards, Mary E.;  Gosling, William D.;  Haberle, Simon;  Hotchkiss, Sara C.;  Huntley, Brian;  Ivory, Sarah J.;  Kershaw, A. Peter;  Kim, Soo-Hyun;  Latorre, Claudio;  Leydet, Michelle;  Lezine, Anne-Marie;  Liu, Kam-Biu;  Liu, Yao;  Lozhkin, A. V.;  McGlone, Matt S.;  Marchant, Robert A.;  Momohara, Arata;  Moreno, Patricio I.;  Mueller, Stefanie;  Otto-Bliesner, Bette L.;  Shen, Caiming;  Stevenson, Janelle;  Takahara, Hikaru;  Tarasov, Pavel E.;  Tipton, John;  Vincens, Annie;  Weng, Chengyu;  Xu, Qinghai;  Zheng, Zhuo;  Jackson, Stephen T.
收藏  |  浏览/下载:20/0  |  提交时间:2019/11/27
Nonstationary Hydrologic Behavior in Forested Watersheds Is Mediated by Climate-Induced Changes in Growing Season Length and Subsequent Vegetation Growth 期刊论文
WATER RESOURCES RESEARCH, 2018, 54 (8) : 5359-5375
作者:  Hwang, Taehee;  Martin, Katherine L.;  Vose, James M.;  Wear, David;  Miles, Brian;  Kim, Yuri;  Band, Lawrence E.
收藏  |  浏览/下载:7/0  |  提交时间:2019/04/09
growing season length  hydrologic non-stationarity  vegetation phenology  GIMMS NDVI3g  RHESSys  
Piezo2 channel-Merkel cell signaling modulates the conversion of touch to itch 期刊论文
SCIENCE, 2018, 360 (6388) : 530-+
作者:  Feng, Jing;  Luo, Jialie;  Yang, Pu;  Du, Junhui;  Kim, Brian S.;  Hu, Hongzhen
收藏  |  浏览/下载:1/0  |  提交时间:2019/11/27